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

Rafael A. Cubas, Joseph C. Mudd, Anne Laure Savoye, Matthieu Perreau, Julien Van Grevenynghe, Talibah Metcalf, Elizabeth Connick, Amie Meditz, Gordon J. Freeman, Guillermo Abesada-Terk, Jeffrey M. Jacobson, Ari D. Brooks, Shane Crotty, Jacob D. Estes, Giuseppe Pantaleo, Michael M. Lederman, Elias K. Haddad

Research output: Contribution to journalArticle

239 Scopus citations

Abstract

The majority of HIV-infected individuals fail to produce protective antibodies and have diminished responses to new immunizations. We report here that even though there is an expansion of follicular helper T (T FH) 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 T FH cell function. In fact, we show that engagement of PD-1 on T FH 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 T FH cell-mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on T FH cells. These results demonstrate a role for T FH 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.

Original languageEnglish (US)
Pages (from-to)494-499
Number of pages6
JournalNature medicine
Volume19
Issue number4
DOIs
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Cubas, R. A., Mudd, J. C., Savoye, A. L., Perreau, M., Van Grevenynghe, J., Metcalf, T., Connick, E., Meditz, A., Freeman, G. J., Abesada-Terk, G., Jacobson, J. M., Brooks, A. D., Crotty, S., Estes, J. D., Pantaleo, G., Lederman, M. M., & Haddad, E. K. (2013). Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nature medicine, 19(4), 494-499. https://doi.org/10.1038/nm.3109