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

• Published in: PLoS pathogens Vol. 11; no. 1; p. e1004517
• Main Authors: Clouthier, Derek L, Zhou, Angela C, Wortzman, Michael E, Luft, Olga, Levy, Gary A, Watts, Tania H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2015; Public Library of Science (PLoS)
• Subjects: Animals; Antigens; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - physiology; Cell Differentiation - genetics; Cells, Cultured; Chronic Disease; Cloning; Cricetinae; Deaths; Experiments; Female; Genetic aspects; Glucocorticoid-Induced TNFR-Related Protein - physiology; Health aspects; Host-virus relationships; Immune system; Immunity, Humoral - genetics; Infections; Lymphocytes; Lymphocytic Choriomeningitis - genetics; Lymphocytic Choriomeningitis - immunology; Lymphocytic choriomeningitis virus - immunology; Lymphopoiesis - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Prevention; Proteins; Rodents; Spleen; T cell receptors; T cells; T-Lymphocytes, Helper-Inducer - physiology; Tumor necrosis factor; Viral infections; Virus Diseases - genetics; Virus Diseases - immunology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004517

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.