PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors

Abstract

The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8 ؉ T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8 ؉ T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8 ؉ T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8 ؉ T cells with markedly lower PD-1 expression. TPs, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 up-regulation was also associated with reduced perforin and IFN-␥ production, as well as decreased HIV-specific effector memory CD8 ؉ T-cell proliferation in TPs but not LTNPs. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8 ؉ T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 up-regulation mediates HIV-specific CD8 ؉ T-cell exhaustion. IntroductionCD8 ϩ T cells play a critical role in clearing human immunodeficiency virus (HIV) infection in vivo. 1 In general, typical progressors (TPs) have insufficient CD8 ϩ T-cell responses to HIV and fail to maintain durable control of the HIV load, whereas long-term nonprogressors (LTNPs) preferentially maintain functional HIVspecific CD8 ϩ T cells that can persistently control viral replication. [2][3][4][5][6][7][8][9][10] During the CD8 ϩ T-cell response to HIV, there is a complex process of memory CD8 ϩ T-cell differentiation. 11 On the basis of CD45RA and CCR7 surface marker expression and relative function, 4 subpopulations of memory CD8 ϩ T cells are proposed to exist: naive CD45RA ϩ CCR7 ϩ T cells, central memory CD45RA Ϫ CCR7 ϩ T (T CM ) cells, effector memory CD45RA Ϫ CCR7 Ϫ T (T EM ) cells, and terminally differentiated effector CD45RA ϩ CCR7 Ϫ T (T EM RA) cells. [12][13][14][15] The T CM subpopulation readily differentiates into proliferating effector cells and homes to T-cell areas of the secondary lymphoid organs, but it has little or no effector function. The T EM subset has selectively lost constitutive CCR7 expression and produces high levels of perforin, IFN-␥, and IL-4 within hours of antigenic stimulation. The T EM RA subset, the T EM subpopulation that expresses CD45RA, can produce high levels of perforin. Thus, T EM cells are characterized by rapid effector function. Champagne et al 16 have demonstrated that chronic HIV-1 infection affects the differentiation pattern of different CD8 ϩ T-cell subsets; however, the molecular mechanisms of how this process occurs remain undefined.Memory T-cell responses are an important component of protective immunity against viral infection. However, memory T-cell responses generated during chronic viral infection often show defects in antiviral function and skewed differentiation of the memory T-cell subsets. [16][17][18] For example, the proportion ...

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

“…Consistent with recent studies in mice and humans, [5][6][7][8][9]27 our data confirm that blocking the PD-1/PD-L1 pathway has potential therapeutic value in tumor immunotherapy. At least in NSCLC conditions, blocking the PD-1/PD-L1 pathway was more effective than blocking the PD-1/PD-L2 pathway.…”

“…Increasing apoptosis of tumor-infiltrating CD8 1 T cells and blocking the PD-1/PD-L1 pathway cannot abrogate apoptosis Because PD-1 upregulation has been reported to be more sensitive to apoptosis, resulting in a deficiency of CD8 1 T cells in controlling virus replication, [6][7][8][9] we tested apoptosis of different CD8 1 T cells induced by anti-CD3. Tumor-infiltrating CD8 1 T cells exhibited much higher apoptosis rates than peripheral blood CD8 1 T cells from either healthy control or patients with NSCLC (all P,0.01; Figure 4a).…”

“…5 Increasing evidence demonstrates that upregulation of the PD-1 inhibitory receptor mediates HIV-specific CD8 1 T-cell functional exhaustion and CD8 1 T cell is apoptosis-sensitive, resulting in an impairment of CD8 1 T cell's ability to control virus replication. [6][7][8][9] Involvement of the PD-1 pathway has also been shown during hepatitis B and C virus infection [10][11][12][13] with PD-L1 expression demonstrated in situ on a wide variety of solid tumors including pancreas, lung, ovarian and bladder tumors. [14][15][16][17][18] Studies relating PD-L1 expression on tumors to disease outcome show that PD-L1 expression strongly correlates with unfavorable prognosis in kidney, bladder, gastric and pancreatic cancer.…”

Modulating Co-Stimulation

“…81 The correlations between PD-1 expression and clinical outcome were recently strengthened by the finding that long-term HIV nonprogressors exhibited functional HIV-specific memory CD8ϩ T cells with markedly lower PD-1 expression, whereas typical progressors showed upregulated PD-1 expression correlating with a reduction in CD4 T-cell number and increased plasma viral load. 82 Furthermore, PD-1 upregulation was associated with reduced perforin and interferon-gamma production, as well as decreased HIV-specific effector memory CD8ϩ T-cell proliferation in progressors. Blockade of this pathway reinvigorates the exhausted T cells, allowing them to expand and produce effector cytokines and reduce viral load.…”

“…Blockade of this pathway reinvigorates the exhausted T cells, allowing them to expand and produce effector cytokines and reduce viral load. [82][83][84][85] Given the essential role of co-stimulation in the activation of pathogenic T cells, the development of therapeutic strategies aiming at the selective blockade of costimulatory molecules has been a focal point of studies of autoimmune diseases. Blockade of co-stimulation would in fact have the advantage of targeting those T cells that have already received the first signal regardless of the specific antigen triggering the TCR.…”