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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin HIV AIDS. Author manuscript; available in PMC Mar 1, 2011.
Published in final edited form as:
PMCID: PMC2886291
NIHMSID: NIHMS203437

Th17 Cell Dynamics in HIV Infection

Abstract

Purpose of Review

Th17 cells are a newly identified subtype of CD4+ T cells that respond to bacterial and fungal antigens and are important in mucosal immunology. Because HIV infection results in loss of CD4+ T cells as well as disruption to the GI tract that causes microbial translocation and immune activation, Th17 cells potentially play an important role in HIV pathogenesis. Here we examine the relationship between Th17 cells and HIV disease pathogenesis.

Recent findings

Th17 cells are preferentially lost from the GI tract of HIV-infected individuals, which is not entirely due to direct infection, as Th17 cells can be infected in vivo, but are not preferentially infected. Long-term HAART can result in restoration of Th17 cells in the GI, which may be associated with better disease prognosis. Furthermore, other cells, such as Vδ1 T cells, can make IL-17 in vivo during HIV infection and may contribute to anti-bacterial immunity after loss of Th17 cells.

Summary

Recent studies have improved our understanding of the role for Th17 cells during HIV infection, however more studies are needed to discern better the detrimental consequences of loss of Th17 cells during HIV infection.

Keywords: HIV, Th17, T cell, microbial translocation, immune activation

Introduction

HIV infection is characterized by a progressive loss of CD4+ T cells and massive dysregulation of the immune system, which ultimately leads to AIDS. HIV pathogenesis is extraordinarily complex and begins its course of destruction during the acute phase of infection, which is characterized by robust viral replication concurrent with rapid infection and depletion of mucosal CD4+ T cells [14]. Since the primary co-receptor for HIV is CCR5, HIV specifically targets and replicates in CCR5+CD4+ memory T cells, which comprise the majority of CD4+ T cells in mucosal associated lymphoid tissues (MALT)[2,59]. Effector memoryCCR5+T cells mainly reside in extra-lymphoid and effector sites while CCR5− T cells reside in blood and lymph nodes; therefore peripheral CD4+ T cells are relatively spared of massive depletion during the acute phase [2,1013]. During the chronic phase of infection, CD4+ T cells are slowly depleted in lymph nodes, effector tissues and blood, which persists until the majority of CD4+ T cells are depleted and patients develop opportunistic infections and succumb to AIDS.

During the chronic phase of infection, the strongest predictor of disease progression is the level of immune activation during HIV infection. Indeed systemic immune activation is a hallmark of the chronic phase and is characterized by increased cell turnover, high rates of lymphocyte apoptosis, cell cycle dysregulation, and increased levels of proinflammatory cytokines[1416]. Massive infection of CD4+ T cells in MALT is directly associated with inflammation of the mucosal tissues and a breakdown of the mucosal integrity, resulting in microbial translocation from the lumen of the gut into peripheral blood [17]. Translocation of microbial products during HIV infection is demonstrated by an increase in plasma LPS levels and is associated with systemic immune activation [1723]. Hence, regulation of T cell subsets in the mucosa of HIV-infected individuals is of extreme importance in both understanding HIV pathogenesis and developing potential therapies.

Interestingly, loss of CD4+ T cells alone is not sufficient to cause AIDS, as demonstrated by natural host models of simian immunodeficiency virus (SIV). Sooty mangabeys (SM) and African green monkeys (AGM) are natural hosts of SIV, and despite severe depletion of CD4+ T cells in the mucosal tissues during acute SIV infection, these animals do not succumb to AIDS, even in the face of high viral replication [24,25]. Furthermore, chronic depletion of CD4+ T cells in SM does not result in AIDS whether the depletion occurs naturally [26], is antibody-mediated experimentally [27], or by CCR5/CXCR4 dual tropic SIV infection [28]. In all of these studies, animals maintained high viremia, yet did not succumb to AIDS even though CD4+ T cells were lost, suggesting that other facets of disease pathogenesis may be responsible for progression to AIDS in HIV-infected humans and SIV-infected Asian macaques.

Biological relevance of Th17 cells

An important role of mucosal T cells in health has been recently highlighted by numerous studies dedicated to a newly identified subset of CD4+ T cells, Th17 cells, which predominate in the gastrointestinal (GI) tract [2933]. These T cells produce IL-17, which is important in adaptive immunity against extracellular bacteria and fungi [34,35]. Th17 cells are functionally distinct from either Th1 or Th2 cells, and have a crucial role in mucosal immunology, as these cells are potent inducers of tissue inflammation. Th17 cells not only produce IL-17, but they also can secrete TNFα, IL-1, IL-2, IL-21 and IL-22, all strong pro-inflammatory cytokines. These cells have the ability to recruit neutrophils and myeloid cells to effector sites by inducing granulocyte-colony stimulating factor [36], and are involved in epithelial regeneration in mucosal tissues [37]. This regeneration of epithelial cells may be driven by Th17 cells’ ability to induce the expression of claudins, which are components of epithelial tight junctions, and stimulation of defensins and mucin production, all vital for mucosal integrity [38,39]. The importance of Th17 cells in human immunology was recently highlighted by Milner et al., when they showed that individuals with hyper-IgE syndrome (HIES or “Jobs” syndrome) lack IL-17 production by T cells, which leads to susceptibility to certain bacterial and fungal infections [40**].

Indeed, Th17 cells play a crucial role in protection against infections. Ye et al. first demonstrated this, when they infected IL-17 receptor-deficient mice with K. pneumoniae and found that the IL-17 receptor deficient mice had increased susceptibility to K. pneumoniae [36]. Furthermore, Ye et al. demonstrated that this phenotype was directly associated with delayed neutrophil recruitment and reduced expression levels of granulocyte colony-stimulating factor in the lungs of IL-17 receptor-deficient mice [36]. Since these studies, multiple reports have demonstrated the importance of Th17 cells in infection, including multiple bacterial infections, mycobacterium, and fungal infections (summarized in [41]and Table 1). Of note, anti-microbial effects of IL-17 have been independently demonstrated in nearly every bacterial and fungal infection associated with opportunistic infections observed in AIDS patients, albeit these studies have not been performed in the context of HIV/AIDS. Briefly, the effects of IL-17 and/or IL-23 have been associated with reduced bacteria or fungus numbers and/or increased survival for Mycobacterium spp., Salmonella sp., Aspergillus sp. Cryptococcus sp., Pneumocystis sp., Streptococcus, Myscoplasma and Klebseilla pneumoniae, as well as Candida spp. [34,36,4252].

Table 1
Pathogenic microbes whose containment involves Th17 cells

Th17 cells and autoimmunity

Th17 cells, however, can be a double-edged sword. On the one hand, the potent inflammatory properties of these cells are vital to immunity against extracellular bacteria and maintenance of mucosal integrity, while on the other hand unchecked proliferation of these cells can result in autoimmunity and inflammatory conditions leading to pathogenesis. A role for IL-17 was recently described in diseases such as Crohn’s disease, psoriasis, pneumonia and atopic dermatitis even before Th17 cells were characterized [36,5355]. In the case of inflammatory conditions such as Crohn’s disease, ulcerative colitis, and inflammatory bowel disease, there is an association between inflamed mucosa and an increased number of IL-17 producing cells in the gut as compared to healthy controls [37,56,57*59]. Furthermore, it was shown that in inflammatory GI tract diseases such as these, IL-17 is readily measured in patient serum while it is undetectable in healthy patients [56]. The same phenomena have also been observed in other inflammatory conditions, such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis [6063]. Though these studies highlight a negative role for Th17 cells in the context of autoimmunity, lack of Th17 cells results is also detrimental. The possible implications of the anti-microbial role of Th17 cells and the role of these cells during progression to AIDS during HIV infection have been the subject of recent investigations.

HIV and peripheral Th17 cells

The first description of a role for Th17 cells during HIV infection was reported by Maek-a-nantawat et al. in 2007 [64]. Here, the authors stimulated peripheral blood mononuclear cells (PBMC) with phorbol myristate acetate and ionomycin and found that in HIV+ individuals from Thailand, there was a significant increase in IL-17 producing CD4+ T cells compared to seronegative controls. However, it is still unclear as to the role of Th17 cells in peripheral tissues after lentiviral infection, as other studies have shown differing results as to whether Th17 cells are increased, decreased, or not affected in peripheral blood after HIV infection or SIV infection of Asian macaques [65**68]. For instance, Lishomwa et al. assessed the frequency of IL-17 producing CD4+ T cells in HIV-1 infected children, as compared to healthy controls or exposed uninfected individuals [69]. The authors found that in HIV-infected children with plasma viral loads >50 copies/mL there was a significant loss of IL-17 producing PBMC. Furthermore, the authors found a significant negative correlation between the frequency of Th17 cells and HIV plasma viremia, indicating that loss of IL-17 production may be either a cause or effect of high HIV viremia in plasma [69]. The contradictory data on peripheral Th17 cells in HIV, however, may be explained by issues in the quantitative and qualitative assessment of these cells, or possibly timing after infection. Since HIV-infected individuals have a greater frequency of memory T cells compared to uninfected individuals, measuring IL-17 responses in bulk CD4+ T cells vs. memory CD4+ T cells may explain differing results. Another possibility is that at different points after HIV infection, Th17 cells re-circulate, or proliferate in response to a homeostatic drain, which may lead to differing results depending on what phase of infection patients were sampled. A longitudinal assessment of Th17 cells in the periphery during SIV and/or HIV infection is needed in order to better determine the magnitude and tempo of Th17 cell dynamics in peripheral blood.

HIV and mucosal Th17 cells

In order to define better the dynamics and anatomical restrictions of Th17 cells during HIV infection, Brenchley et al. carried out a comprehensive analysis of Th17 cells from the blood, gastrointestinal (GI) tract and bronchoalveolar lavage (BAL) [65**]. In this study, the authors first determined that Th17 cells are found in peripheral blood of healthy individuals, but these cells are comparatively enriched in the GI tract. The authors demonstrated that in both HIV-infected and uninfected individuals, Th17 cells respond to bacterial and fungal antigens such as Staphylococcus aureus, Streptococcal kinase, Tetanus toxoid, and Candida albicans, however Th17 cells were not specific for viral antigens, such as HIV, adenovirus, Cytomegalovirus (CMV), Epstein-Barr virus, and influenza. These data were further confirmed by Yue et al., who demonstrated that in uninfected and chronically HIV-infected individuals, IL-17 was not produced in response to either HIV or CMV antigens [70]. Brenchley et al. went on to show that Th17 cells are preferentially lost from the GI tracts of chronically HIV-infected individuals as compared to uninfected individuals, but this loss of Th17 cells was not observed in BAL or peripheral blood, indicating that this phenomena is specific to the mucosal tissues of the GI tract. The authors furthered their analysis by demonstrating that CD4+ T cells in blood of HIV-infected patients are skewed toward a Th1 phenotype. In order to determine whether HIV preferentially infected Th17 cells, Brenchley et al. sorted IL-17+IFNγ, IL-1IFNγ+, and IL-1IFNγ cells from peripheral blood and determined the infection frequency of each subset using quantitative real-time PCR for HIV DNA. They found that Th17 cells were infected in vivo, however there was no significant differences between the infection frequencies of any functional subset, suggesting that in peripheral blood Th17 cells are not preferentially infected. However, due to limitations with the number of cells available from GI tract biopsies, the infection frequency of Th17 cells in the GI tract was not determined. In order to ascertain if Th17 cells are lost in the GI tract after HIV infection due to direct virus infection or bystander effects such as inflammation and immune activation, further studies are required.

Interestingly, in this study the authors also determined the frequency of Th17 cells in the GI tracts of SIV-infected SM. Brenchley et al. found that there was no preferential loss of Th17 cells, which may suggest a possible mechanism by which SM maintain a healthy GI tract despite overall loss of GI tract CD4+ T cells. Further studies to determine whether Th17 cells are lost from the GI tracts of HIV-infected long-term non-progressors are needed to determine if this may be a mechanism of protection against microbial translocation and immune activation during non-progressive HIV infection.

Indeed, a study by Macal et al. demonstrated that some HIV-infected individuals that were given long term (>5 years) highly active antiretroviral therapy (HAART) were able to reconstitute both Th17 cells and overall frequencies of CD4+ T cells in the GI tract and periphery to healthy levels [71]. In the individuals who received HAART and reconstituted CD4+ T cells, the levels of immune activation, as measured by gene expression levels, were decreased compared to HAART treated, HIV-infected, individuals who did not reconstitute CD4+ T cells. Instead, a low level of immune activation persisted in these individuals when compared to healthy controls. Thus the questions remain whether reconstitution of overall CD4+ T cells and Th17 in the GI tract translates into increased survival, and what happens to viremia after patients stop receiving HAART.

HIV and IL-17 producing γδ T cells

Other T cell subsets may also be contributing to IL-17 production in vivo, and these cells may be important during HIV pathogenesis, as demonstrated by Fenoglio et al. In this study, the authors assessed a role for Vδ1 T cells during HIV infection [72]. Vδ1 T cells are one of two predominant subsets of γδ T cells, which are important for mucosal immunity. During HIV infection, Vδ1 T cells are increased in the peripheral blood, which is suggested to result from mucosal depletion and recirculation [73,74**]. Vδ1 T cells are important to mucosal immunity as they are found in the intraepithelial lymphoid tissue of the mucosa, and mediate immunity against antigens such as Listeria monocytogenes and CMV [75,76]. In this study, Fenoglio et al. found that Vδ1 T cells isolated from HIV-infected patients co-express IL-17 and IFNγ, as well as the Th17 transcription factor RORγt and the Th1 transcription factor TXB21, and are expanded in vivo as compared to healthy patients. Furthermore, they found that these Vδ1 T cells proliferate and produce cytokines in response to Candida albicans and express CCR4 and CCR6, which suggests their ability to home to the GI tract. Of interest, the 30 HIV-infected, HAART-naïve, individuals in this study with >200 CD4+ T cells/mL blood, had varying levels of viremia. The authors suggest that the Vδ1 T cells found in these individuals may be compensating for Th17 function, and that these Vδ1 T cells, expanded in these patients, may play an important role in the control of HIV spreading and defense against opportunistic infections. However, the frequency of these Vδ1 T cells in individuals with AIDS was not studied for comparison. Indeed, a thorough assessment of the association between Vδ1 T cells and IL-17 production and better disease prognosis would be warranted.

Undoubtedly, many further studies are needed to dissect the role of IL-17 producing cells during HIV infection. Favre et al. recently demonstrated that during pathogenic SIV infection of pigtail macaques (PTM), there is a loss of balance between Th17 and regulatory T cell (Treg) populations, whereas the balance is maintained during nonpathogenic SIV infection of AGM [77]. Here the authors found that the loss of balance between Th17 cells and Tregs in PTM was predictive of increased immune activation and disease progression. Indeed, regulation of different CD4+ T cell subsets is likely crucial for homeostasis, albeit discerning different phenotypes is complex. Data on Tregs during HIV infection has been conflicting due to lack of effective markers to adequately identify Tregs. An intriguing study by Wang et al. recently defined GARP, a transmembrane protein that is expressed by Tregs [78]. The authors were able to correlate expression of GARP on activated Tregs with their suppressive capacity, but this did not correlate with FoxP3 expression. Here the authors show that CD25+GARP− T cells produced 3–5 fold higher levels of IL-17 compared to CD25+GARP+ or CD25−GARP−, indicating that GARP may discriminate Tregs from Th17 cells. Furthermore, when the authors assessed FoxP3+ T cells from HIV-infected individuals, they did not find a proportionate increase in GARP+ T cells, suggesting that increases in FoxP3 expression in HIV-infected patients may simply reflect increased immune activation and potentially an increase in IL-17 producing cells, rather than an increase in Tregs. It is clear that both Th17 cells and Tregs play an important role in maintaining a healthy immune system, however studies that define better these cell subsets are needed.

Conclusion

HIV disease pathogenesis is extraordinarily complex and involves both immunodeficiency that leads to opportunistic infections and AIDS as well as excessive inflammation and systemic immune activation. It is not, therefore, surprising that IL-17 producing T cells play a role in HIV pathogenesis(summarized in Table 2). Though there are varying data regarding Th17 cell dynamics in peripheral blood during HIV infection, it is clear that Th17 cells are substantially depleted from the GI tract. Loss of mucosal integrity during HIV and pathogenic SIV infection leads to microbial translocation, which in turn further drives systemic immune activation. Hence Th17 cells may be an excellent target for therapeutic interventions. The extent to which loss of Th17 cells causes dysregulation of mucosal immunity in HIV is still unclear, however Th17 cells are clearly vital in maintaining a healthy mucosa, and loss of these cells is undoubtedly detrimental. However, there are many unanswered questions. First, is it possible to expand Th17 cells in the GI tract after HIV infection? If so, could this expansion increase targets for HIV infection in vivo? Furthermore, could excessive proliferation of Th17 could potentially lead to uncontrolled inflammation in mucosal tissues as observed in chronic inflammatory diseases such as Crohn’s disease and ulcerative colitis? Such inflammation could result in increased destruction to the epithelial barrier of mucosal tissues, enhancing microbial translocation and immune activation. One possibility would be to expand alternative IL-17 producing cells, such as CD8+ T cells, Vδ1 T cells, or to find supplemental cytokines and or chemokines that induce restoration of mucosal tissues without causing systemic inflammation. Given the role for Th17 cells and anti-microbial immunity in mucosal tissues, it is undeniable that loss of these cells impacts immunity during HIV infection, and contribute to opportunistic infections, and a better understanding of the role of Th17 cells during HIV pathogenesis will be critical as new therapeutic interventions are designed.

Table 2
Effects of lentiviral infection on IL-17 producing cell subsets

Acknowledgments

JMB and NRK are funded by the intramural research program, NIAID, NIH. The authors disclose no competing interests.

Bibliography

1. Centlivre M, Sala M, Wain-Hobson S, Berkhout B. In HIV-1 pathogenesis the die is cast during primary infection. Aids. 2007;21:1–11. [PubMed]
2. Picker LJ. Immunopathogenesis of acute AIDS virus infection. Current Opinion in Immunology. 2006;18:3995. [PubMed]
3. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 2005;434:1093–1097. [PubMed]
4. Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, Rosenzweig M, Johnson RP, Desrosiers RC, Lackner AA. Gastrointestinal Tract as a Major Site of CD4+ T Cell Depletion and Viral Replication in SIV Infection. Science. 1998;280:427–431. [PubMed]
5. Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar JB, Planer SL, Legasse A, et al. Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection. J Exp Med. 2007;204:2171–2185. [PMC free article] [PubMed]
6. Chen Z, Zhou P, Ho DD, Landau NR, Marx PA. Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry. J Virol. 1997;71:2705–2714. [PMC free article] [PubMed]
7. Edinger AL, Amedee A, Miller K, Doranz BJ, Endres M, Sharron M, Samson M, Lu ZH, Clements JE, Murphey-Corb M, et al. Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains. Proc Natl Acad Sci U S A. 1997;94:4005–4010. [PMC free article] [PubMed]
8. Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, Kuruppu J, Yazdani J, Migueles SA, Connors M, et al. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol. 2004;78:1160–1168. [PMC free article] [PubMed]
9. Lederman MM, Penn-Nicholson A, Cho M, Mosier D. Biology of CCR5 and its role in HIV infection and treatment. JAMA. 2006;296:815–826. [PubMed]
10. Douek DC, Picker LJ, Koup RA. T cell dynamics in HIV-1 infection. Annu Rev Immunol. 2003;21:265–304. [PubMed]
11. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, et al. CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract. J Exp Med. 2004;200:749–759. [PMC free article] [PubMed]
12. Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, Kuruppu J, Yazdani J, Migueles SA, Connors M, et al. T-Cell Subsets That Harbor Human Immunodeficiency Virus (HIV) In Vivo: Implications for HIV Pathogenesis. J Virol. 2004;78:1160–1168. [PMC free article] [PubMed]
13. Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med. 2006;12:289–295. [PubMed]
14. Paiardini M, Cervasi B, Dunham R, Sumpter B, Radziewicz H, Silvestri G. Cell-cycle dysregulation in the immunopathogenesis of AIDS. Immunol Res. 2004;29:253–268. [PubMed]
15. Paiardini M, Cervasi B, Sumpter B, McClure HM, Sodora DL, Magnani M, Staprans SI, Piedimonte G, Silvestri G. Perturbations of cell cycle control in T cells contribute to the different outcomes of simian immunodeficiency virus infection in rhesus macaques and sooty mangabeys. J Virol. 2006;80:634–642. [PMC free article] [PubMed]
16. Hurtrel B, Petit F, Arnoult D, Muller-Trutwin M, Silvestri G, Estaquier J. Apoptosis in SIV infection. Cell Death Differ. 2005;12 (Suppl 1):979–990. [PubMed]
17. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–1371. [PubMed]
18. Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe? Nat Immunol. 2006;7:235–239. [PubMed]
19. Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B, Landay A, Martin J, Sinclair E, Asher AI, et al. Plasma Levels of Bacterial DNA Correlate with Immune Activation and the Magnitude of Immune Restoration in Persons with Antiretroviral ÄêTreated HIV Infection. The Journal of Infectious Diseases. 2009;199:1177–1185. [PMC free article] [PubMed]
20. Baroncelli S, Galluzzo CM, Pirillo MF, Mancini MG, Weimer LE, Andreotti M, Amici R, Vella S, Giuliano M, Palmisano L. Microbial translocation is associated with residual viral replication in HAART-treated HIV+ subjects with <50copies/ml HIV-1 RNA. J Clin Virol. 2009 [PubMed]
21. Marchetti G, Bellistri GM, Borghi E, Tincati C, Ferramosca S, La Francesca M, Morace G, Gori A, Monforte AD. Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS. 2008;22:2035–2038. [PubMed]
22. Ancuta P, Kamat A, Kunstman KJ, Kim E-Y, Autissier P, Wurcel A, Zaman T, Stone D, Mefford M, Morgello S, et al. Microbial Translocation Is Associated with Increased Monocyte Activation and Dementia in AIDS Patients. PLoS ONE. 2008;3:e2516. [PMC free article] [PubMed]
23. Papasavvas E, Pistilli M, Reynolds G, Bucki R, Azzoni L, Chehimi J, Janmey PA, DiNubile MJ, Ondercin J, Kostman JR, et al. Delayed loss of control of plasma lipopolysaccharide levels after therapy interruption in chronically HIV-1-infected patients. AIDS. 2009;23:369–375. [PMC free article] [PubMed]
24. Gordon SN, Klatt NR, Bosinger SE, Brenchley JM, Milush JM, Engram JC, Dunham RM, Paiardini M, Klucking S, Danesh A, et al. Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys. J Immunol. 2007;179:3026–3034. [PMC free article] [PubMed]
25. Pandrea IV, Gautam R, Ribeiro RM, Brenchley JM, Butler IF, Pattison M, Rasmussen T, Marx PA, Silvestri G, Lackner AA, et al. Acute Loss of Intestinal CD4+ T Cells Is Not Predictive of Simian Immunodeficiency Virus Virulence. J Immunol. 2007;179:3035–3046. [PMC free article] [PubMed]
26. Sumpter B, Dunham R, Gordon S, Engram J, Hennessy M, Kinter A, Paiardini M, Cervasi B, Klatt N, McClure H, et al. Correlates of preserved CD4(+) T cell homeostasis during natural, nonpathogenic simian immunodeficiency virus infection of sooty mangabeys: implications for AIDS pathogenesis. J Immunol. 2007;178:1680–1691. [PubMed]
27. Klatt NR, Villinger F, Bostik P, Gordon SN, Pereira L, Engram JC, Mayne A, Dunham RM, Lawson B, Ratcliffe SJ, et al. Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys. J Clin Invest. 2008;118:2039–2049. [PMC free article] [PubMed]
28. Milush JM, Reeves JD, Gordon SN, Zhou D, Muthukumar A, Kosub DA, Chacko E, Giavedoni LD, Ibegbu CC, Cole KS, et al. Virally Induced CD4+ T Cell Depletion Is Not Sufficient to Induce AIDS in a Natural Host. J Immunol. 2007;179:3047–3056. [PubMed]
29. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003;278:1910–1914. [PubMed]
30. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–240. [PMC free article] [PubMed]
31. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT. Interleukin 17-producing CD4+effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–1132. [PubMed]
32. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–1141. [PMC free article] [PubMed]
33. Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13:139–145. [PubMed]
34. Huang W, Na L, Fidel PL, Schwarzenberger P. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis. 2004;190:624–631. [PubMed]
35. Chung DR, Kasper DL, Panzo RJ, Chitnis T, Grusby MJ, Sayegh MH, Tzianabos AO. CD4+ T cells mediate abscess formation in intra-abdominal sepsis by an IL-17-dependent mechanism. J Immunol. 2003;170:1958–1963. [PubMed]
36. Ye P, Garvey PB, Zhang P, Nelson S, Bagby G, Summer WR, Schwarzenberger P, Shellito JE, Kolls JK. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol. 2001;25:335–340. [PubMed]
37. Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte J-M, Diepolder H, Marquardt A, Jagla W, Popp A, et al. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2006;290:G827–838. [PubMed]
38. Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, Mizoguchi A. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. The Journal of Clinical Investigation. 2008;118:534–544. [PMC free article] [PubMed]
39. Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem. 2003;278:17036–17043. [PubMed]
**40. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452:773–776. This manuscript suggested that the inability to produce Th17 cells in vivo resulted in increased susceptibility to extracellular bacterial pathogens. [PMC free article] [PubMed]
41. Curtis MM, Way SS. Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology. 2009;126:177–185. [PMC free article] [PubMed]
42. Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ, Odden AR, Shellito JE, Bagby GJ, Nelson S, et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med. 2005;202:761–769. [PMC free article] [PubMed]
43. Wu Q, Martin RJ, Rino JG, Breed R, Torres RM, Chu HW. IL-23-dependent IL-17 production is essential in neutrophil recruitment and activity in mouse lung defense against respiratory Mycoplasma pneumoniae infection. Microbes Infect. 2007;9:78–86. [PMC free article] [PubMed]
44. Lu YJ, Gross J, Bogaert D, Finn A, Bagrade L, Zhang Q, Kolls JK, Srivastava A, Lundgren A, Forte S, et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog. 2008;4:e1000159. [PMC free article] [PubMed]
45. Schulz SM, Kohler G, Holscher C, Iwakura Y, Alber G. IL-17A is produced by Th17, gammadelta T cells and other CD4-lymphocytes during infection with Salmonella enterica serovar Enteritidis and has a mild effect in bacterial clearance. Int Immunol. 2008;20:1129–1138. [PubMed]
46. Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, Shen F, Eaton SM, Gaffen SL, Swain SL, et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol. 2007;8:369–377. [PubMed]
47. Kleinschek MA, Muller U, Brodie SJ, Stenzel W, Kohler G, Blumenschein WM, Straubinger RK, McClanahan T, Kastelein RA, Alber G. IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12. J Immunol. 2006;176:1098–1106. [PubMed]
48. Rudner XL, Happel KI, Young EA, Shellito JE. Interleukin-23 (IL-23)-IL-17 cytokine axis in murine Pneumocystis carinii infection. Infect Immun. 2007;75:3055–3061. [PMC free article] [PubMed]
49. Wozniak TM, Ryan AA, Britton WJ. Interleukin-23 restores immunity to Mycobacterium tuberculosis infection in IL-12p40-deficient mice and is not required for the development of IL-17-secreting T cell responses. J Immunol. 2006;177:8684–8692. [PubMed]
50. Happel KI, Lockhart EA, Mason CM, Porretta E, Keoshkerian E, Odden AR, Nelson S, Ramsay AJ. Pulmonary interleukin-23 gene delivery increases local T-cell immunity and controls growth of Mycobacterium tuberculosis in the lungs. Infect Immun. 2005;73:5782–5788. [PMC free article] [PubMed]
51. Eyerich K, Foerster S, Rombold S, Seidl HP, Behrendt H, Hofmann H, Ring J, Traidl-Hoffmann C. Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. J Invest Dermatol. 2008;128:2640–2645. [PubMed]
52. Zelante T, De Luca A, Bonifazi P, Montagnoli C, Bozza S, Moretti S, Belladonna ML, Vacca C, Conte C, Mosci P, et al. IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol. 2007;37:2695–2706. [PubMed]
53. Sallusto F, Lanzavecchia A. Human Th17 cells in infection and autoimmunity. Microbes Infect. 2009;11:620–624. [PubMed]
54. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103:1345–1352. [PMC free article] [PubMed]
55. Albanesi C, Cavani A, Girolomoni G. IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: synergistic or antagonist effects with IFN-gamma and TNF-alpha. J Immunol. 1999;162:494–502. [PubMed]
56. Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, Bamba T, Fujiyama Y. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52:65–70. [PMC free article] [PubMed]
*57. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Fili L, Ferri S, Frosali F, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204:1849–1861. This manuscript provides in depth phenotypic and functional analysis of Th17 cells in humans. [PMC free article] [PubMed]
58. Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R, Kitazume MT, Nakazawa A, Sugita A, Koganei K, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. 2008;57:1682–1689. [PubMed]
59. Monteleone G, Fina D, Caruso R, Pallone F. New mediators of immunity and inflammation in inflammatory bowel disease. Curr Opin Gastroenterol. 2006;22:361–364. [PubMed]
60. Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, Takabayashi K, Iwamoto I. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum. 2000;43:2455–2463. [PubMed]
61. Wong CK, Ho CY, Li EK, Lam CW. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus. 2000;9:589–593. [PubMed]
62. Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol. 2008;127:385–393. [PubMed]
63. Muller A, Lamprecht P. Interleukin-17 in chronic inflammatory and autoimmune diseases: rheumatoid arthritis, Crohn’s disease and Wegener’s granulomatosis. Z Rheumatol. 2008;67:72–74. [PubMed]
64. Maek ANW, Buranapraditkun S, Klaewsongkram J, Ruxrungtham K. Increased interleukin-17 production both in helper T cell subset Th17 and CD4-negative T cells in human immunodeficiency virus infection. Viral Immunol. 2007;20:66–75. [PubMed]
**65. Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, Asher TE, Scheinberg P, Price DA, Hage CA, Kholi LM, et al. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood. 2008;112:2826–2835. This manuscript demonstrates the differential depletion of Th17 cells in the GI tracts of HIV-infected humans. [PMC free article] [PubMed]
66. Cecchinato V, Trindade CJ, Laurence A, Heraud JM, Brenchley JM, Ferrari MG, Zaffiri L, Tryniszewska E, Tsai WP, Vaccari M, et al. Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol. 2008;1:279–288. [PMC free article] [PubMed]
67. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE, Godinez I, Sankaran S, Paixao TA, Gordon MA, et al. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med. 2008;14:421–428. [PMC free article] [PubMed]
68. Ndhlovu LCa, Chapman JMa, Jha ARa, Snyder-Cappione JEa, Pagan Mb, Leal FEa, Boland BSa, Norris PJbc, Rosenberg MGd, Nixon DFa. Suppression of HIV-1 plasma viral load below detection preserves IL-17 producing T cells in HIV-1 infection. [PMC free article] [PubMed]
69. Ndhlovu LC, Chapman JM, Jha AR, Snyder-Cappione JE, Pagan M, Leal FE, Boland BS, Norris PJ, Rosenberg MG, Nixon DF. Suppression of HIV-1 plasma viral load below detection preserves IL-17 producing T cells in HIV-1 infection. AIDS. 2008;22:990–992. [PMC free article] [PubMed]
70. Yue FY, Merchant A, Kovacs CM, Loutfy M, Persad D, Ostrowski MA. Virus-specific interleukin-17-producing CD4+ T cells are detectable in early human immunodeficiency virus type 1 infection. J Virol. 2008;82:6767–6771. [PMC free article] [PubMed]
71. Macal M, Sankaran S, Chun TW, Reay E, Flamm J, Prindiville TJ, Dandekar S. Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses. Mucosal Immunol. 2008;1:475–488. [PubMed]
72. Fenoglio D, Poggi A, Catellani S, Battaglia F, Ferrera A, Setti M, Murdaca G, Zocchi MR. Vdelta1 T lymphocytes producing IFN-gamma and IL-17 are expanded in HIV-1-infected patients and respond to Candida albicans. Blood. 2009;113:6611–6618. [PubMed]
73. Nilssen DE, Muller F, Oktedalen O, Froland SS, Fausa O, Halstensen TS, Brandtzaeg P. Intraepithelial gamma/delta T cells in duodenal mucosa are related to the immune state and survival time in AIDS. J Virol. 1996;70:3545–3550. [PMC free article] [PubMed]
*74. Gioia C, Agrati C, Casetti R, Cairo C, Borsellino G, Battistini L, Mancino G, Goletti D, Colizzi V, Pucillo LP, et al. Lack of CD27-CD45RA-V gamma 9V delta 2+ T cell effectors in immunocompromised hosts and during active pulmonary tuberculosis. J Immunol. 2002;168:1484–1489. This manuscript highlights alternative subsets of T cells that can produce IL17. [PubMed]
75. Nishimura Y, Brown CR, Mattapallil JJ, Igarashi T, Buckler-White A, Lafont BA, Hirsch VM, Roederer M, Martin MA. Resting naive CD4+ T cells are massively infected and eliminated by X4-tropic simian-human immunodeficiency viruses in macaques. Proc Natl Acad Sci U S A. 2005;102:8000–8005. [PMC free article] [PubMed]
76. Matsuzaki G, Yamada H, Kishihara K, Yoshikai Y, Nomoto K. Mechanism of murine Vgamma1+ gamma delta T cell-mediated innate immune response against Listeria monocytogenes infection. Eur J Immunol. 2002;32:928–935. [PubMed]
77. Favre D, Lederer S, Kanwar B, Ma Z-M, Proll S, Kasakow Z, Mold J, Swainson L, Barbour JD, Baskin CR, et al. Critical Loss of the Balance between Th17 and T Regulatory Cell Populations in Pathogenic SIV Infection. PLoS Pathog. 2009;5:e1000295. [PMC free article] [PubMed]
78. Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A. 2009;106:13439–13444. [PMC free article] [PubMed]
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