Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade

Abstract

chronic infection ͉ lymphocytic choriomeningitis virus ͉ T cell exhaustion ͉ PD-1 ͉ T cell memory R ecent studies have revealed an important role for the negative regulatory molecule programmed death-1 (PD-1) in T cell exhaustion during chronic viral infections (1). PD-1, a member of the CD28:CTLA-4 family of costimulatory and coinhibitory receptors, contains both immunotyrosine inhibitory motif (ITIM) and immunotyrosine switch motif (ITSM) signaling motifs, recruits the phosphatase Shp-2, and can deliver inhibitory signals (1). PD-1 interacts with two ligands, PD-ligand 1 (PD-L1), expressed by a wide variety of cells, and PD-L2, expressed mainly by macrophages and DC (1). A role for PD-1 in regulating T cell responses to chronic viral infections was identified by using lymphocytic choriomeningitis virus (LCMV) infection of mice (2). PD-1 was highly overexpressed on exhausted CD8 T cells from chronically infected animals compared with functional memory CD8 T cells from mice that had resolved acute infection. In vivo blockade of the PD-1:PD-L pathway during chronic LCMV infection led to a dramatic increase in the number and functionality of virus-specific CD8 T cells and enhanced control of infection (2). Other animal models of viral infection also supported a major role for the PD-1 pathway in regulating antiviral T cell responses (3, 4). These observations were quickly extended to primates and humans. Simian immunodeficiency virus (SIV)-, HIV-, hepatitis C virus (HCV)-, and hepatitis B virus (HBV)-specific CD8 T cells express elevated levels of PD-1 compared with CD8 T cells specific for nonpersisting pathogens such as influenza virus or vaccinia virus (5-12). In vitro blockade of PD-1:PD-L interactions reverses exhaustion of HIV-, HBV-, and HCV-specific T cells, and the proliferative capacity of these virus-specific T cell populations is dramatically improved. In light of these recent findings, PD-1 has emerged as not only a major regulator of T cell exhaustion during chronic infection, but also as an important potential therapeutic target.At least two models have been proposed for the mechanism of reversal of exhaustion by PD-1:PD-L blockade (13). In one model, PD-1:PD-L blockade reprograms all exhausted T cells, converting them to functional antiviral effector T cells. In a second model, PD-1:PD-L blockade selectively expands and/or enhances function of a subset of exhausted CD8 T cells. In the present work, we have addressed this question directly. We have identified two subsets of exhausted CD8 T cells during chronic LCMV infection in mice that differ in expression of PD-1 and CD44. One subset that expressed intermediate levels of PD-1 and high levels of CD44 (PD-1 Int CD44 Hi ) could be reinvigorated by blocking PD-1:PD-L interactions. In contrast, the second subset was PD-1 Hi but CD44Int and responded poorly to PD-1 pathway blockade. Thus, our data suggest that the cellular mechanism of reinvigorated T cell responses during chronic viral infection is by selective expansion of one subset of exhausted CD8...

Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors

“…8E); however, the intensity of PD-1 on effector CD8 + T cells was significantly decreased in mice simultaneously treated with PD-1 and Tim-3 (Fig. 8E), supporting the previous finding that the expression levels of PD-1 dictate the functional ability of CD8 + T cells (9). In agreement with the enhanced functionality of Ag-specific effector CD8 + T cells, we observed significantly improved viral control and reduced splenomegaly in mice simultaneously treated with PD-1 and Tim-3 (Fig.…”

“…For example, in the case of hepatitis C virus infection, highly PD-1 + and profoundly dysfunctional CD8 + T cells were located at the sites where the relevant Ag persisted at high levels, such as the liver (8). Although blockade of PD-1/programmed death ligand (PD-L)1 interactions during the chronic phase of infection is a promising approach to reinvigorating the exhausted Ag-specific CD8 + T cells, such an intervention resulted in little effect for these highly exhausted PD-1 Hi CD8 + T cells (8,9). A recent study using the lymphocytic choriomeningitis virus (LCMV) provided a likely explanation for the relatively limited effect of the PD-1 blockade: exhausted CD8 + T cells are coregulated by multiple inhibitory receptors during chronic infection (10).…”

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…This further underscores cancer immunotherapy as a double-edged sword in which patients and clinicians must weigh the risk of immunotoxicity against the benefit of tumor destruction 35 . By comparison, PD-1 blockade is likely to reinvigorate a previously overactive immune system 32 ; studies of T cell exhaustion in chronic infection show that PD-1 functions to limit effector T cell-mediated inflammatory injury 36 . Studies of individuals with cancer have not yet compared T cell exhaustion profiles from patients treated with PD-1 with those from patients receiving CTLA-4 blockade as treatment.…”

Tumor-infiltrating Tim-3+ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

“…Indeed, cells with high versus low levels of PD-1 appear phenotypically and functionally distinct. Thus, according to a previous report, 35 two subpopulations of exhausted CD8 C T cells with high or intermediate expression of PD-1 were identified during chronic LCMV infection in mice. Although both subsets were functionally exhausted compared to memory CD8 C T cells in acute infection, the PD-1 int subset had higher proliferative potential and was preferentially reinvigorated by PD-L1 blockade than were the PD-1 hi cells, indicating that the exhaustion status of T cells can be tuned by the relative expression level of PD-1.…”