Follicular Regulatory CD8 T Cells Impair the Germinal Center Response in SIV and Ex Vivo HIV Infection.

Brodie Miles,Joy M Folkvord,Elizabeth Connick,David N Levy,Shannon M Miller,Eva G Rakasz,Pamela J Skinner,Guido Silvestri

doi:10.1371/journal.ppat.1005924

Abstract

During chronic HIV infection, viral replication is concentrated in secondary lymphoid follicles. Cytotoxic CD8 T cells control HIV replication in extrafollicular regions, but not in the follicle. Here, we show CXCR5hiCD44hiCD8 T cells are a regulatory subset differing from conventional CD8 T cells, and constitute the majority of CD8 T cells in the follicle. This subset, CD8 follicular regulatory T cells (CD8 TFR), expand in chronic SIV infection, exhibit enhanced expression of Tim-3 and IL-10, and express less perforin compared to conventional CD8 T cells. CD8 TFR modestly limit HIV replication in follicular helper T cells (TFH), impair TFH IL-21 production via Tim-3, and inhibit IgG production by B cells during ex vivo HIV infection. CD8 TFR induce TFH apoptosis through HLA-E, but induce less apoptosis than conventional CD8 T cells. These data demonstrate that a unique regulatory CD8 population exists in follicles that impairs GC function in HIV infection.

Highlights

In chronic HIV and SIV infection, viral replication is concentrated in B cell follicles in secondary lymphoid tissues [1,2,3,4,5], factors that promote this are not fully understood
HIV is able to hide in various niches throughout the body. One such niche are CD4 T cells residing in the follicles and germinal centers of secondary lymphoid tissues
Using flow cytometry counting beads to show the average of 3 experiments, we confirmed that CD8 TFR did not increase numerically in the context of ex vivo HIV infection (S1 Fig)

Summary

Introduction

In chronic HIV and SIV infection, viral replication is concentrated in B cell follicles in secondary lymphoid tissues [1,2,3,4,5], factors that promote this are not fully understood. We have previously shown that virus-specific CD8 T cells are present at lower frequencies inside the follicle compared to outside the follicle in HIV and SIV infection [2, 9], which may contribute to impaired viral clearance in the follicle. We have previously reported that CD4 follicular regulatory T cells (TFR) are increased in number, exhibit heighted regulatory capabilities, and impair TFH proliferation and function in ex vivo HIV and in vivo SIV infection [7]. We hypothesized that follicular CD8 T cells may have regulatory functions that further contribute to immune dysregulation in chronic HIV infection

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Conclusion