Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells.
Virus-specific CD8(+) T-cell responses play a pivotal role in limiting viral replication. Alterations in these responses, such as decreased cytolytic function, inappropriate maturation, and limited proliferative ability could reduce their ability to control viral replication. Here, we report on the capacity of HIV-specific CD8(+) T cells to secrete cytokines and proliferate in response to HIV antigen stimulation. We find that a large proportion of HIV-specific CD8(+) T cells that produce cytokines in response to cognate antigen are unable to divide and die during a 48-hour in vitro culture. This lack of proliferative ability of HIV-specific CD8(+) T cells is defined by surface expression of CD57 but not by absence of CD28 or CCR7. This inability to proliferate in response to antigen cannot be overcome by exogenous interleukin-2 (IL-2) or IL-15. Furthermore, CD57 expression on CD8(+) T cells, CD4(+) T cells, and NK cells is a general marker of proliferative inability, a history of more cell divisions, and short telomeres. We suggest, therefore, that the increase in CD57(+) HIV-specific CD8(+) T cells results from chronic antigen stimulation that is a hallmark of HIV infection. Thus, our studies define a phenotype associated with replicative senescence in HIV-specific CD8(+) T cells, which may have broad implications to other conditions associated with chronic antigenic stimulation.
Brenchley
Jason M
JM
Vaccine Research Center and the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Karandikar
Nitin J
NJ
Betts
Michael R
MR
Ambrozak
David R
DR
Hill
Brenna J
BJ
Crotty
Laura E
LE
Casazza
Joseph P
JP
Kuruppu
Janaki
J
Migueles
Stephen A
SA
Connors
Mark
M
Roederer
Mario
M
Douek
Daniel C
DC
Koup
Richard A
RA
D017209:Apoptosis / Q000276:immunology*; D018106:CD28 Antigens / Q000032:analysis; D018959:CD57 Antigens / Q000096:biosynthesis* / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D016922:Cellular Senescence; D016207:Cytokines / Q000378:metabolism; D015488:HIV Antigens / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D010641:Phenotype; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000032:analysis
C515370:CCR7 protein, human; D018106:CD28 Antigens; D018959:CD57 Antigens; D016207:Cytokines; D015488:HIV Antigens; D054400:Receptors, CCR7; D019707:Receptors, Chemokine