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Inadequate T follicular cell help impairs B cell immunity during HIV infection

Nature Medicine volume 19, pages 494–499 (2013)Cite this article

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Abstract

The majority of HIV-infected individuals fail to produce protective antibodies and have diminished responses to new immunizations1,2,3. We report here that even though there is an expansion of follicular helper T (TFH) cells in HIV-infected individuals, the cells are unable to provide adequate B cell help. We found a higher frequency of programmed cell death ligand 1 (PD-L1)+ germinal center B cells from lymph nodes of HIV-infected individuals suggesting a potential role for PD-1–PD-L1 interaction in regulating TFH cell function. In fact, we show that engagement of PD-1 on TFH cells leads to a reduction in cell proliferation, activation, inducible T-cell co-stimulator (ICOS) expression and interleukin-21 (IL-21) cytokine secretion. Blocking PD-1 signaling enhances HIV-specific immunoglobulin production in vitro. We further show that at least part of this defect involves IL-21, as addition of this cytokine rescues antibody responses and plasma cell generation in vitro. Our results suggest that deregulation of TFH cell–mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on TFH cells. These results demonstrate a role for TFH cell impairment in HIV pathogenesis and suggest that enhancing their function could have a major impact on the outcome and control of HIV infection, preventing future infections and improving immune responses to vaccinations.

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Figure 1: TFH cells from HIV-infected subjects are unable to provide appropriate B cell help.
Figure 2: Ex vivo characterization of TFH cells and B cells in lymph nodes from HIV-infected and uninfected individuals.
Figure 3: Ligating PD-1 on TFH cells leads to a decrease in cell proliferation, activation and cytokine secretion.
Figure 4: Supplementation with IL-21 restores IgG production in cocultures from HIV-infected lymph nodes.

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Acknowledgements

We thank W. Ryzner, R. Bordi and D. Brown for sample collection. We also thank K. Kusser and Y. Shi from the Flow Cytometry Core at Vaccine & Gene Therapy Institute Florida for their help with sorting all the samples. We are grateful to R. Debernardo (Case Western Reserve University and University Hospitals Case Medical Center) for obtaining the HIV-uninfected lymph nodes and to B. Rodriguez for his help with the infected lymph node samples. This study was supported in part by US National Institutes of Health (NIH) contract HHSN272201100017C, NIH-1P01 AI080192, U19AI082630, 2P01 AI056299 and R01 AI096966. This work was also supported by the Case Western Reserve University Center for AIDS Research (AI 36219) and by the Cleveland Immunopathogenesis Consortium (AI 76174).

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Authors and Affiliations

  1. Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA

    Rafael A Cubas, Julien van Grevenynghe, Talibah Metcalf & Elias K Haddad

  2. Division of Infectious Diseases, Center for AIDS Research, Case Western Reserve University/University Hospitals, Case Medical Center, Cleveland, Ohio, USA

    Joseph C Mudd & Michael M Lederman

  3. Division of Immunology and Allergy, Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

    Anne-Laure Savoye, Matthieu Perreau & Giuseppe Pantaleo

  4. Division of Infectious Diseases, University of Colorado Denver, Colorado, USA

    Elizabeth Connick & Amie Meditz

  5. Department of Medical Oncology, Dana-Faber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Gordon J Freeman

  6. Robert and Carol Weissman Cancer Center, Martin Memorial Health Systems, Stuart, Florida, USA

    Guillermo Abesada-Terk Jr

  7. Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

    Jeffrey M Jacobson

  8. Department of Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

    Ari D Brooks

  9. Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA

    Shane Crotty

  10. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, California, USA

    Shane Crotty

  11. The AIDS and Cancer Virus Program, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA

    Jacob D Estes

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Contributions

R.A.C. designed and performed experiments, analyzed data and wrote the manuscript. J.C.M. helped perform the phenotyping of TFH and lymph node cell populations. A.-L.S. and M.P. helped provide preliminary data and performed the Luminex assays. J.v.G. helped in the coculture assays and ELISAs. T.M. assisted in the tonsil processing. E.C. and A.M. provided tissue sections for immunohistochemistry; G.J.F. provided valuable reagents and intellectual input. J.M.J. provided lymph node samples and discussion; A.D.B. performed surgeries on HIV infected lymph nodes; G.A.-T. Jr. provided intellectual input and valuable tonsil samples. S.C. assisted in experimental design, discussion and analysis of data. J.D.E. performed immunohistochemistry. G.P. and M.M.L. provided valuable discussion, designed experiments, provided conceptual advice and edited the manuscript. E.K.H. conceived of and directed the research, analyzed data and helped write the manuscript.

Corresponding author

Correspondence to Elias K Haddad.

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Cubas, R., Mudd, J., Savoye, AL. et al. Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat Med 19, 494–499 (2013). https://doi.org/10.1038/nm.3109

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