SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection

Abstract

Programmed death-1 (PD-1) is a critical mediator of virus-specific CD8 ؉ T-cell exhaustion. Here, we examined the expression of PD-1 on simian immunodeficiency virus (SIV)-specific CD8 ؉ T cells and its possible involvement in regulation of cytokine production, proliferation, and survival of these cells. The majority of SIV-specific CD8 ؉ T cells expressed a PD-1 high phenotype, independent of their differentiation status, in all tissues tested. PD-1 expression gradually declined on CD8 ؉ T cells specific for SIV-derived epitopes that had undergone mutational escape, indicating that antigen-specific TCR stimulation is the primary determinant of PD-1 expression. SIV-specific PD-1 high CD8 ؉ T cells produced IFN-␥, TNF-␣, and IL-2 under cognate peptide stimulation. While CD8 ؉ T cells that proliferated in response to antigen had a PD-1 high phenotype, it was determined that there was a reduced proliferative capacity of PD-1 high compared with PD-1 low SIVspecific CD8 ؉ T cells. PD-1 high SIV-specific CD8 ؉ T cells were highly susceptible to IntroductionVirus-specific CD8 ϩ T cells are the predominant effectors through which the immune system controls viral infections. 1,2 While several lines of evidence indicate that human immunodeficiency virus (HIV)-specific CD8 ϩ T cells are involved in the control of HIV replication, 3-10 several reports have focused on intrinsic defects in these cells to explain their failure to clear the virus, thereby leading to progression to acquired immunodeficiency syndrome (AIDS) in all infected individuals. [11][12][13][14] Similarly, simian immunodeficiency virus (SIV)-specific CD8 ϩ T cells contribute substantially to the partial control of viremia in rhesus macaques; depletion of CD8 ϩ T cells results in increased viremia in SIV-infected animals, 15,16 while viral escape at targeted epitopes accelerates disease progression and death in vaccinated animals. 4 Furthermore, in acute SIV infection, cytotoxic SIV-specific CD8 ϩ T cells appear concurrently with the waning of early viremia. 17 As in human infection with HIV, functional defects in SIV-specific CD8 ϩ T cells have been reported, potentially explaining why virtually all SIV-infected rhesus macaques progress to simian AIDS and death despite a readily measurable CD8 ϩ T-cell response. [17][18][19][20] Therefore, understanding factors that regulate the function(s) of SIV-and HIV-specific CD8 ϩ T cells is critical in the fight against AIDS.Chronic viral infection with ongoing antigenic stimulation often results in exhaustion of virus-specific CD8 ϩ T cells. 21,22 Chronically stimulated virus-specific CD8 ϩ T cells express only low levels of receptors for IL-7 and IL-15 23 and lose the ability to maintain homeostatic proliferation. In addition, they lose the ability to produce key cytokines that are critical for the maintenance of CD8 ϩ T-cell memory. 24 In humans, the function and phenotype of chronically stimulated CD8 ϩ T cells differ among viral infections. HIV-specific CD8 ϩ T cells are less polyfunctional and more sensitive ...

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

“…5C). The level of spontaneous caspase 3 activation was highest in the PD-1 Hi subset compared with the PD-1 Int subset of LCMV-specific CD8 T cells from chronically infected mice, consistent with previous reports for HIV-and SIV-specific CD8 T cells (6,20). The small subset of PD-1 Lo GP33-specific CD8 T cells present in the chronically infected mice displayed a lower level of ACasp3 staining, but this level was still greater than that found in GP33-specific CD8 T cells from LCMV Arm immune mice (Fig.…”

“…PD-L1 blockade in vivo alone or in combination with therapeutic vaccination reduces the level of apoptosis of exhausted CD8 T cells (19). In addition, higher levels of PD-1 expression correlate with an increased rate of apoptosis in HIV-specific CD8 T cells, and engaging PD-1 on SIV-specific CD8 T cells increases cell death (6,20). Based on these observations, we examined the PD-1…”

TIMs: central regulators of immune responses

“…Sorting of TIM-3 + and TIM-3 Ϫ populations revealed that HIV-specifi c T cells expressing high amounts of TIM-3 secreted less IFN ␥ than did TIM-3 Ϫ cell, choriomeningitis virus in mice, simian immune defi ciency syndrome in rhesus macaques, and HIV in humans, each of which demonstrated that blocking this pathway increased T cell responses, improved viral control in vivo, and enhanced the survival and proliferation of antigen-specifi c CD8 + T cells in vitro (2,3,20,21). Although PD-1 expression appeared to identify a population of T cells entering into exhaustion, not all exhausted cells expressed PD-1 (3).…”

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

“…Programmed cell death-1 (PD-1) has been identified as a major cell-surface inhibitory receptor that regulates CD8 + T cell exhaustion (2). The levels of PD-1 expression on CD8 + T cells critically correlate with Ag load and the severity of exhaustion (3)(4)(5)(6)(7). 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).…”