Human and simian immunodeficiency viruses (HIV and SIV) exploit follicular lymphoid regions by establishing high levels of viral replication and dysregulating humoral immunity. Follicular regulatory T cells (TFR) are a recently characterized subset of lymphocytes that influence the germinal centre response through interactions with follicular helper T cells (TFH). Here, utilizing both human and rhesus macaque models, we show the impact of HIV and SIV infection on TFR number and function. We find that TFR proportionately and numerically expand during infection through mechanisms involving viral entry and replication, TGF-β signalling, low apoptosis rates and the presence of regulatory dendritic cells. Further, TFR exhibit elevated regulatory phenotypes and impair TFH functions during HIV infection. Thus, TFR contribute to inefficient germinal centre responses and inhibit HIV and SIV clearance.
Bibliographical noteFunding Information:
We thank Mario Santiago for valuable discussions and comments. We also thank David Watkins and Nancy Wilson for sharing reagents and animal specimens. MVC (cat #11580), bicyclam (cat # 8128) and RAL (cat # 11680) were obtained through the NIH AIDS reagent program. This work was funded by NIH/NIAID grants R01 AI096966 to E.C. and P.J.S., R01 AI078783A to D.N.L., 5T32AI007447-22 T32 to B.M., T32 5T32AI007447 to M.C., T32 AI007405 to S.M.M. NIH/NHLBI PHS grant HL103286 to T.A., and the Wisconsin National Primate Research Center (WNPRC) P51OD011106. Cell sorting was performed by the University of Colorado Cancer Flow Cytometry Shared Resource, which is supported by the Cancer Center Support Grant P30CA046934 and the Skin Diseases Research Cores Grant P30AR057212. The funding source played no role in experimental design or data analysis.
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