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J Immunol. 2015 Dec 15;195(12):5625-36. doi: 10.4049/jimmunol.1501524. Epub 2015 Nov 6.

Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.

Author information

  • 1Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
  • 2Institut National de la Recherche Scientifique, Institut Armand-Frappier, Laval H7V 1B7, Quebec, Canada;
  • 3Department of Immunology and the Duke Human Vaccine Institute, Duke University, Durham, NC 27710;
  • 4Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
  • 5Service d'Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland;
  • 6Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
  • 7Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada; Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada;
  • 8Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec H3H 2R9, Canada; Research Institute, McGill University Health Centre, Montreal, Quebec H3H 2R9, Canada; Division of Hematology, McGill University Health Centre, Montreal, Quebec H3H 2R9, Canada;
  • 9International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
  • 10Immunology Laboratory, Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
  • 11HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
  • 12Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093; and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037.
  • 13Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987; elias.elhaddad@drexelmed.edu.

Abstract

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.

PMID:
26546609
PMCID:
PMC4670798
DOI:
10.4049/jimmunol.1501524
[PubMed - indexed for MEDLINE]
Free PMC Article
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