GITR intrinsically sustains early type 1 and late follicular helper CD4 T cell accumulation to control a chronic viral infection.

Derek L Clouthier,Tania H Watts,Olga Luft,Angela C Zhou,Gary A Levy,Michael E Wortzman,Christopher M Walker

doi:10.1371/journal.ppat.1004517

Abstract

CD4 T cells are critical for control of persistent infections; however, the key signals that regulate CD4 T help during chronic infection remain incompletely defined. While several studies have addressed the role of inhibitory receptors and soluble factors such as PD-1 and IL-10, significantly less work has addressed the role of T cell co-stimulatory molecules during chronic viral infection. Here we show that during a persistent infection with lymphocytic choriomeningitis virus (LCMV) clone 13, mice lacking the glucocorticoid-induced tumor necrosis factor receptor related protein (GITR) exhibit defective CD8 T cell accumulation, increased T cell exhaustion and impaired viral control. Differences in CD8 T cells and viral control between GITR+/+ and GITR-/- mice were lost when CD4 T cells were depleted. Moreover, mixed bone marrow chimeric mice, as well as transfer of LCMV epitope-specific CD4 or CD8 T cells, demonstrated that these effects of GITR are largely CD4 T cell-intrinsic. GITR is dispensable for initial CD4 T cell proliferation and differentiation, but supports the post-priming accumulation of IFNγ+IL-2+ Th1 cells, facilitating CD8 T cell expansion and early viral control. GITR-dependent phosphorylation of the p65 subunit of NF-κB as well as phosphorylation of the downstream mTORC1 target, S6 ribosomal protein, were detected at day three post-infection (p.i.), and defects in CD4 T cell accumulation in GITR-deficient T cells were apparent starting at day five p.i. Consistently, we pinpoint IL-2-dependent CD4 T cell help for CD8 T cells to between days four and eight p.i. GITR also increases the ratio of T follicular helper to T follicular regulatory cells and thereby enhances LCMV-specific IgG production. Together, these findings identify a CD4 T cell-intrinsic role for GITR in sustaining early CD8 and late humoral responses to collectively promote control of chronic LCMV clone 13 infection.

Highlights

During chronic viral infections, exemplified by the clone 13 variant of lymphocytic choriomeningitis virus (LCMV cl 13), persistent antigen presentation results in the functional exhaustion of the T cell response, characterized by persistent upregulation of inhibitory molecules and a progressive loss of T cell effector functions [1]
The natural rodent pathogen LCMV clone 13 causes a persistent viral infection in mice and has successfully predicted several immunological factors that are relevant to human chronic viral infection such as HIV
LCMV clone 13 infection is controlled by cell-mediated and humoral immune responses by day 60–90 post-infection in CD4 T cellsufficient mice. While it has been known for several years that CD4 T cell help is critical for control of LCMV clone 13, research to date has been largely limited to the regulatory factors that contribute to late CD4 T cell dysfunction, with little knowledge of the role of T cell co-stimulatory factors in sustaining CD4 T cells to help cell-mediated and humoral immune responses

Summary

Introduction

During chronic viral infections, exemplified by the clone 13 variant of lymphocytic choriomeningitis virus (LCMV cl 13), persistent antigen presentation results in the functional exhaustion of the T cell response, characterized by persistent upregulation of inhibitory molecules and a progressive loss of T cell effector functions [1]. Co-stimulatory TNFR family members are of particular interest in this regard because they are often induced upon antigen receptor signaling, leading to their co-expression with inhibitory receptors during a persistent infection [8,9,10]. CD4 T cell help is critical for the control of chronic infections. While CD4 cells are clearly implicated in the control of chronic viral infections, the co-stimulatory signals that contribute to CD4 T cell help remain poorly defined. Evidence to date suggests that there is significant heterogeneity in the potency and mechanisms of T cell modulation by members of the TNFR superfamily during chronic viral infection [8, 9, 15,16,17,18]

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Results

Discussion

Conclusion