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

Petrovas C, Price DA, Mattapallil J, Ambrozak DR, Geldmacher C, Cecchinato V, Vaccari M, Tryniszewska E, Gostick E, Roederer M, Douek DC, Morgan SH, Davis SJ, Franchini G, Koup RA. (2007), Blood. 110, 928-36

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-gamma, TNF-alpha, 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) SIV-specific CD8+ T cells. PD-1(high) SIV-specific CD8+ T cells were highly susceptible to cell death leading to loss of such cells after in vitro stimulation. Thus, PD-1 is a negative regulator of SIV-specific CD8+ T cells, operating predominantly through the induction of cell death. Manipulation of the interaction of PD-1 with its ligands could thus potentially restore the CD8+ T-cell responses in SIV infection.

Key figure: PD-1high CM9-specific CD8+ T cells are highly susceptible to activation-induced cell death

(B) Histograms representing the CFSE dilution in annexin V−CM9+CD8+ T cells cultured alone or stimulated with CM9 peptide in the absence or presence of an anti-PD-1 antibody (20 μg/mL) (left panel). The levels of annexin V positivity on CM9+CD8+ T cells, under the same treatment conditions, are also shown (left panel). The effect of treatment with the anti-PD-1 on the PD-1high and PD-1low CM9+CD8+ T cells in a 6-day culture is shown in the right panel. Data from 1 of 2 macaques tested are shown.