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

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

Nature medicine (2013-03-12)
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
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 (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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Mouse IgG2a Isotype Control from murine myeloma, clone UPC-10, purified immunoglobulin, buffered aqueous solution
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