Abstract
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.
Highlights
Human and simian immunodeficiency viruses (HIV and SIV) exploit follicular lymphoid regions by establishing high levels of viral replication and dysregulating humoral immunity
An expansion of TFH cells has been observed in HIV infection[11] and simian immunodeficiency virus (SIV) infection[12], yet this expansion does not correlate with improved germinal centre (GC) responses
This expansion is due to a combination of factors, including viral entry and replication, Treg acquisition of CXCR5, transforming growth factor (TGF)-b signalling, TFR proliferation, low apoptosis rates and increased regulatory dendritic cell (DC) activity
Summary
Human and simian immunodeficiency viruses (HIV and SIV) exploit follicular lymphoid regions by establishing high levels of viral replication and dysregulating humoral immunity. In HIV-infected subjects, the percentage of activated (HLA-DR þ CD38 þ ) LN CD4 þ T cells, as previously determined by flow cytometry[33], did not correlate with number of Treg or TFR and was inversely correlated with GC TFR in the average tissue cross-section (Supplementary Fig. 1c). In both TFH ) populations and TFR compared in mock-spinoculated with cells at day 2 (Fig. 3d).
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