Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection

Abstract

T reg cells effectively maintain CD8 T cell exhaustion during chronic LCMV infection, but blockade of PD-1 is critical for elimination of infected cells.

TIGIT predominantly regulates the immune response via regulatory T cells

“…This observation is in line with our previous study showing that the dysfunctional phenotype of CD8 + TILs is diminished after Treg depletion (25) and with a recent study showing that Tregs modify the tumor microenvironment to promote CD8 + T cell dysfunction (31). Similarly, Tregs have recently been shown to play an important role in the maintenance of T cell dysfunction in chronic LCMV infection (32). Thus, a key function of Tregs in chronic disease settings may be to drive the dysfunctional phenotype in effector CD8 + T cells in order to prevent immunopathology.…”

PD-1 Upregulated on Regulatory T Cells during Chronic Virus Infection Enhances the Suppression of CD8+ T Cell Immune Response via the Interaction with PD-L1 Expressed on CD8+ T Cells

“…Although T reg cell-mediated suppression of antiviral T cells during chronic virus infection has been reported (4,11,39,40), the underlying mechanism has not been intensively investigated. We found that either PD-1 blockade on chronic T reg cells or PD-L1 deficiency on CD8 + T cells dramatically diminished the suppression of T cell CD8 + T cells, suppressed CD8 + T cell immune response.…”

“…Moreover, T reg cells suppress antiviral T cell response against chronic viruses, as previously reviewed (10). It was recently reported that depletion of T reg cells in the mice chronically infected with lymphocytic meningitis virus (LCMV) resulted in a significant expansion of functional LCMV-specific CD8 + T cells (11), demonstrating the strong suppressive activity of T reg cells during chronic virus infection. However, the molecular mechanisms of T reg cell-mediated immune suppression during chronic pathogen infection are poorly understood.…”

Requirement of Treg-intrinsic CTLA4/PKCη signaling pathway for suppressing tumor immunity

“…The numbers of tumor-infiltrating CD11c Exhaustion is a hallmark of dysfunctional CD8 + T cells in the TME (18)(19)(20). As Tregs might promote the development of exhaustion through diverse and ill-defined mechanisms (21,22), we questioned whether the enhanced TIL function observed in the presence of Prkch Figure 4C), analysis by an unpaired t test revealed a significant difference (P = 0.042; data not shown). These results suggest that PKCη deficiency reduces the ability of Tregs to suppress the priming and proliferation of antigen-specific CD8 + TILs.…”