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 Estes, Giuseppe Pantaleo, Michael M. Lederman, Elias K. Haddad

Research output: Contribution to journalArticle

224 Citations (Scopus)

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 1 2013
Externally publishedYes

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HIV Infections
Immunity
B-Lymphocytes
Cells
HIV
CD274 Antigen
Inducible T-Cell Co-Stimulator Protein
Cytokines
Immunization
Deregulation
Antibodies
Cell proliferation
Cell death
Immunoglobulins
Chemical activation
Germinal Center
Ligands
Plasmas
Defects
Plasma Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cubas, R. A., Mudd, J. C., Savoye, A. L., Perreau, M., Van Grevenynghe, J., Metcalf, T., ... 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

Inadequate T follicular cell help impairs B cell immunity during HIV infection. / Cubas, Rafael A.; Mudd, Joseph C.; Savoye, Anne Laure; Perreau, Matthieu; Van Grevenynghe, Julien; Metcalf, Talibah; Connick, Elizabeth; Meditz, Amie; Freeman, Gordon J.; Abesada-Terk, Guillermo; Jacobson, Jeffrey M.; Brooks, Ari D.; Crotty, Shane; Estes, Jacob; Pantaleo, Giuseppe; Lederman, Michael M.; Haddad, Elias K.

In: Nature Medicine, Vol. 19, No. 4, 01.04.2013, p. 494-499.

Research output: Contribution to journalArticle

Cubas, RA, Mudd, JC, Savoye, AL, Perreau, M, Van Grevenynghe, J, Metcalf, T, Connick, E, Meditz, A, Freeman, GJ, Abesada-Terk, G, Jacobson, JM, Brooks, AD, Crotty, S, Estes, J, Pantaleo, G, Lederman, MM & Haddad, EK 2013, 'Inadequate T follicular cell help impairs B cell immunity during HIV infection', Nature Medicine, vol. 19, no. 4, pp. 494-499. https://doi.org/10.1038/nm.3109
Cubas RA, Mudd JC, Savoye AL, Perreau M, Van Grevenynghe J, Metcalf T et al. Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nature Medicine. 2013 Apr 1;19(4):494-499. https://doi.org/10.1038/nm.3109
Cubas, Rafael A. ; Mudd, Joseph C. ; Savoye, Anne Laure ; Perreau, Matthieu ; Van Grevenynghe, Julien ; Metcalf, Talibah ; Connick, Elizabeth ; Meditz, Amie ; Freeman, Gordon J. ; Abesada-Terk, Guillermo ; Jacobson, Jeffrey M. ; Brooks, Ari D. ; Crotty, Shane ; Estes, Jacob ; Pantaleo, Giuseppe ; Lederman, Michael M. ; Haddad, Elias K. / Inadequate T follicular cell help impairs B cell immunity during HIV infection. In: Nature Medicine. 2013 ; Vol. 19, No. 4. pp. 494-499.
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