FoxP3+ CD4+ cells promote CD8 T cell exhaustion during chronic infection (105.5)

Abstract

Abstract Understanding the factors that guide T cell exhaustion may provide opportunities to modulate immune responses during chronic infections. We analyzed the contribution of CD4+ FoxP3+ cells (Tregs), to the process of CD8 T cell exhaustion during chronic lymphocytic choriomeningitis virus (LCMV) infection. Tregs have been shown be the master regulators of immune tolerance. However, a possible suppressive role for these cells during chronic infections is still not very well defined, and most studies show correlations, but not direct causations. Normally, LCMV chronically viremic mice experience a pronounced CD8 T cell exhaustion. We showed for the first time that specific ablation of Tregs (in FoxP3DTR mice) after the onset of a chronic viral infection results in a significant rescue of viral-specific CD8 T cell responses. In addition, PD-1 blockade together with Treg depletion resulted in significant reduction of viral loads, greater than PD-L1 blockade alone. This suggests that Tregs and the PD- pathway control CD8 T cell exhaustion by different mechanisms. The CD8 T cell rescue observed after Treg depletion is dependent on B7 signaling, CD4+ cells, and the presence of viral antigen, suggesting a general role for these factors in maintaining CD8 T cell exhaustion during persistent infections. Our data also indicates a general mechanism that may be used by Tregs to suppress self-specific T cell responses during immune homeostasis.