SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection.
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.
Petrovas
Constantinos
C
Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases/NIH, 40 Convent Drive, Bethesda, MD 20892, USA. petrovasc@mail.nih.gov
Price
David A
DA
Mattapallil
Joseph
J
Ambrozak
David R
DR
Geldmacher
Christof
C
Cecchinato
Valentina
V
Vaccari
Monica
M
Tryniszewska
Elzbieta
E
Gostick
Emma
E
Roederer
Mario
M
Douek
Daniel C
DC
Morgan
Sara H
SH
Davis
Simon J
SJ
Franchini
Genoveffa
G
Koup
Richard A
RA
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D008253:Macaca mulatta; D010455:Peptides / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome; D015302:Simian Immunodeficiency Virus / Q000276:immunology*
D015703:Antigens, CD; D000956:Antigens, Viral; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D000939:Epitopes; D010455:Peptides