Ligand-independent exhaustion of killer immunoglobulin-like receptor-positive CD8+ T cells in human immunodeficiency virus type 1 infection.
Virus-specific CD8(+) T cells play a central role in the control of viral infections, including human immunodeficiency virus type 1 (HIV-1) infection. However, despite the presence of strong and broad HIV-specific CD8(+) T-cell responses in chronic HIV-1 infection, these cells progressively lose critical effector functions and fail to clear the infection. Mounting evidence suggests that the upregulation of several inhibitory regulatory receptors on the surface of CD8(+) T cells during HIV-1 infection may contribute directly to the impairment of T-cell function. Here, we investigated the role of killer immunoglobulin receptors (KIR), which are expressed on NK cells and on CD8(+) T cells, in regulating CD8(+) T-cell function in HIV-1 infection. KIR expression was progressively upregulated on CD8(+) T cells during HIV-1 infection and correlated with the level of viral replication. Expression of KIR was associated with a profound inhibition of cytokine secretion, degranulation, proliferation, and activation by CD8(+) T cells following stimulation with T-cell receptor (TCR)-dependent stimuli. In contrast, KIR(+) CD8(+) T cells responded potently to TCR-independent stimulation, demonstrating that these cells are functionally competent. KIR-associated suppression of CD8(+) T-cell function was independent of ligand engagement, suggesting that these regulatory receptors may constitutively repress TCR activation. This ligand-independent repression of TCR activation of KIR(+) CD8(+) T cells may represent a significant barrier to therapeutic interventions aimed at improving the quality of the HIV-specific CD8(+) T-cell response in infected individuals.
Alter
Galit
G
Partners AIDS Research Center, Massachusetts General Hospital, 149 13th Street, Boston, MA 02129, USA. galter@partners.org
Rihn
Suzannah
S
Streeck
Hendrik
H
Teigen
Nickolas
N
Piechocka-Trocha
Alicja
A
Moss
Kristin
K
Cohen
Kristen
K
Meier
Angela
A
Pereyra
Florencia
F
Walker
Bruce
B
Altfeld
Marcus
M
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008024:Ligands; D008213:Lymphocyte Activation; D054340:Receptors, KIR / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology; D014779:Virus Replication
D016207:Cytokines; D008024:Ligands; D054340:Receptors, KIR