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J Exp Med. Feb 1, 1994; 179(2): 589–600.
PMCID: PMC2191378

Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell- mediated immunity

Abstract

BALB/c mice infected with the intracellular protozoan Leishmania major mount a T helper cell 2 (Th2) response that fails to control growth of the parasite and results in the development of visceral leishmaniasis. Separation of CD4+ T cells into CD45RBhigh and CD45RBlow subsets showed that the L. major-specific Th2 cells were contained within the CD45RBlow population as these cells produced high levels of antigen- specific interleukin 4 (IL-4) in vitro and transferred a nonhealing response to L. major-infected C.B-17 scid mice. In contrast, the CD45RBhighCD4+ population contained L. major-reactive cells that produced interferon gamma (IFN-gamma) in vitro and transferred a healing Th1 response to L. major-infected C.B-17 scid mice. Transfer of the Th1 response by the CD45RBhigh population was inhibited by the CD45RBlow population by a mechanism that was dependent on IL-4. These data indicate that L. major-specific Th1 cells do develop in BALB/c mice, but their functional expression is actively inhibited by production of IL-4 by Th2 cells. In this response, the suppressed Th1 cells can be phenotypically distinguished from the suppressive Th2 cells by the level of expression of CD45RB. Although the CD45RBhigh population mediated a protective response to L. major, C.B-17 scid mice restored with this population developed a severe inflammatory response in the colon that was independent of L. major infection, and was prevented by cotransfer of the CD45RBlow population. The colitis appeared to be due to a dysregulated Th1 response as anti-IFN-gamma, but not anti-IL-4, prevented it. Taken together, the data show that the CD4+ T cell population identified by high level expression of the CD45RB antigen contains cells that mediate both protective and pathogenic Th1 responses and that the reciprocal CD45RBlow population can suppress both of these responses. Whether suppression of cell- mediated immunity is beneficial or not depends on the nature of the stimulus, being deleterious during L. major infection but crucial for control of potentially pathogenic inflammatory responses developing in the gut.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Spickett GP, Brandon MR, Mason DW, Williams AF, Woollett GR. MRC OX-22, a monoclonal antibody that labels a new subset of T lymphocytes and reacts with the high molecular weight form of the leukocyte-common antigen. J Exp Med. 1983 Sep 1;158(3):795–810. [PMC free article] [PubMed]
  • Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. [PubMed]
  • Gajewski TF, Fitch FW. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol. 1988 Jun 15;140(12):4245–4252. [PubMed]
  • Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. [PMC free article] [PubMed]
  • Peleman R, Wu J, Fargeas C, Delespesse G. Recombinant interleukin 4 suppresses the production of interferon gamma by human mononuclear cells. J Exp Med. 1989 Nov 1;170(5):1751–1756. [PMC free article] [PubMed]
  • Vercelli D, Jabara HH, Lauener RP, Geha RS. IL-4 inhibits the synthesis of IFN-gamma and induces the synthesis of IgE in human mixed lymphocyte cultures. J Immunol. 1990 Jan 15;144(2):570–573. [PubMed]
  • Tanaka T, Hu-Li J, Seder RA, Fazekas de St Groth B, Paul WE. Interleukin 4 suppresses interleukin 2 and interferon gamma production by naive T cells stimulated by accessory cell-dependent receptor engagement. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5914–5918. [PMC free article] [PubMed]
  • Powrie F, Menon S, Coffman RL. Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo. Eur J Immunol. 1993 Sep;23(9):2223–2229. [PubMed]
  • Coffman RL. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development. Immunol Rev. 1982;69:5–23. [PubMed]
  • Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol. 1993 Nov;5(11):1461–1471. [PubMed]
  • Cherwinski HM, Schumacher JH, Brown KD, Mosmann TR. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987 Nov 1;166(5):1229–1244. [PMC free article] [PubMed]
  • Abrams JS, Pearce MK. Development of rat anti-mouse interleukin 3 monoclonal antibodies which neutralize bioactivity in vitro. J Immunol. 1988 Jan 1;140(1):131–137. [PubMed]
  • Heinzel FP, Sadick MD, Mutha SS, Locksley RM. Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7011–7015. [PMC free article] [PubMed]
  • Coffman RL, Varkila K, Scott P, Chatelain R. Role of cytokines in the differentiation of CD4+ T-cell subsets in vivo. Immunol Rev. 1991 Oct;123:189–207. [PubMed]
  • Müller I, Pedrazzini T, Kropf P, Louis J, Milon G. Establishment of resistance to Leishmania major infection in susceptible BALB/c mice requires parasite-specific CD8+ T cells. Int Immunol. 1991 Jun;3(6):587–597. [PubMed]
  • Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. [PubMed]
  • Morrissey PJ, Charrier K, Braddy S, Liggitt D, Watson JD. CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med. 1993 Jul 1;178(1):237–244. [PMC free article] [PubMed]
  • Liew FY. Functional heterogeneity of CD4+ T cells in leishmaniasis. Immunol Today. 1989 Feb;10(2):40–45. [PubMed]
  • Milon G, Titus RG, Cerottini JC, Marchal G, Louis JA. Higher frequency of Leishmania major-specific L3T4+ T cells in susceptible BALB/c as compared with resistant CBA mice. J Immunol. 1986 Feb 15;136(4):1467–1471. [PubMed]
  • Lohoff M, Sommer F, Solbach W, Röllinghoff M. Coexistence of antigen-specific TH1 and TH2 cells in genetically susceptible BALB/c mice infected with Leishmania major. Immunobiology. 1989 Oct;179(4-5):412–421. [PubMed]
  • Morris L, Troutt AB, McLeod KS, Kelso A, Handman E, Aebischer T. Interleukin-4 but not gamma interferon production correlates with the severity of murine cutaneous leishmaniasis. Infect Immun. 1993 Aug;61(8):3459–3465. [PMC free article] [PubMed]
  • Sher A, Gazzinelli RT, Oswald IP, Clerici M, Kullberg M, Pearce EJ, Berzofsky JA, Mosmann TR, James SL, Morse HC., 3rd Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol Rev. 1992 Jun;127:183–204. [PubMed]
  • Sher A, Fiorentino D, Caspar P, Pearce E, Mosmann T. Production of IL-10 by CD4+ T lymphocytes correlates with down-regulation of Th1 cytokine synthesis in helminth infection. J Immunol. 1991 Oct 15;147(8):2713–2716. [PubMed]
  • Street NE, Mosmann TR. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J. 1991 Feb;5(2):171–177. [PubMed]
  • Birkeland ML, Johnson P, Trowbridge IS, Puré E. Changes in CD45 isoform expression accompany antigen-induced murine T-cell activation. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6734–6738. [PMC free article] [PubMed]
  • Lee WT, Yin XM, Vitetta ES. Functional and ontogenetic analysis of murine CD45Rhi and CD45Rlo CD4+ T cells. J Immunol. 1990 May 1;144(9):3288–3295. [PubMed]
  • Bradley LM, Atkins GG, Swain SL. Long-term CD4+ memory T cells from the spleen lack MEL-14, the lymph node homing receptor. J Immunol. 1992 Jan 15;148(2):324–331. [PubMed]
  • Mason D, Powrie F. Memory CD4+ T cells in man form two distinct subpopulations, defined by their expression of isoforms of the leucocyte common antigen, CD45. Immunology. 1990 Aug;70(4):427–433. [PMC free article] [PubMed]
  • Bottomly K, Luqman M, Greenbaum L, Carding S, West J, Pasqualini T, Murphy DB. A monoclonal antibody to murine CD45R distinguishes CD4 T cell populations that produce different cytokines. Eur J Immunol. 1989 Apr;19(4):617–623. [PubMed]
  • Varkila K, Chatelain R, Leal LM, Coffman RL. Reconstitution of C.B-17 scid mice with BALB/c T cells initiates a T helper type-1 response and renders them capable of healing Leishmania major infection. Eur J Immunol. 1993 Jan;23(1):262–268. [PubMed]
  • Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993 Oct 22;75(2):253–261. [PubMed]
  • Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. [PubMed]
  • Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992 Oct 22;359(6397):693–699. [PMC free article] [PubMed]
  • Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770–774. [PMC free article] [PubMed]
  • Powrie F, Mason D. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset. J Exp Med. 1990 Dec 1;172(6):1701–1708. [PMC free article] [PubMed]
  • Fowell D, Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med. 1993 Mar 1;177(3):627–636. [PMC free article] [PubMed]

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