Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection.
Cytotoxic CD8(+) T cells (CTLs) contain virus infections through the release of granules containing both perforin and granzymes. T cell 'exhaustion' is a hallmark of chronic persistent viral infections including HIV. The inhibitory regulatory molecule, T cell Immunoglobulin and Mucin domain containing 3 (Tim-3) is induced on HIV-specific T cells in chronic progressive infection. These Tim-3 expressing T cells are dysfunctional in terms of their capacities to proliferate or to produce cytokines. In this study, we evaluated the effect of Tim-3 expression on the cytotoxic capabilities of CD8(+) T cells in the context of HIV infection. We investigated the cytotoxic capacity of Tim-3 expressing T cells by examining 1) the ability of Tim-3(+) CD8(+) T cells to make perforin and 2) the direct ability of Tim-3(+) CD8(+) T cells to kill autologous HIV infected CD4(+) target cells. Surprisingly, Tim-3(+) CD8(+) T cells maintain higher levels of perforin, which was mainly in a granule-associated (stored) conformation, as well as express high levels of T-bet. However, these cells were also defective in their ability to degranulate. Blocking the Tim-3 signalling pathway enhanced the cytotoxic capabilities of HIV specific CD8(+) T cells from chronic progressors by increasing; a) their degranulation capacity, b) their ability to release perforin, c) their ability to target activated granzyme B to HIV antigen expressing CD4(+) T cells and d) their ability to suppress HIV infection of CD4(+) T cells. In this latter effect, blocking the Tim-3 pathway enhances the cytotoxcity of CD8(+) T cells from chronic progressors to the level very close to that of T cells from viral controllers. Thus, the Tim-3 receptor, in addition to acting as a terminator for cytokine producing and proliferative functions of CTLs, can also down-regulate the CD8(+) T cell cytotoxic function through inhibition of degranulation and perforin and granzyme secretion.
Department of Immunology, University of Toronto, Toronto, Ontario, Canada. ali.sakhdari@utoronto.ca
Ali
A
Sakhdari
Shariq
S
Mujib
Bahareh
B
Vali
Feng Yun
FY
Yue
Sonya
S
MacParland
Kiera
K
Clayton
Richard Bradley
RB
Jones
Jun
J
Liu
Erika Yue
EY
Lee
Erika
E
Benko
Colin
C
Kovacs
Jennifer
J
Gommerman
Rupert
R
Kaul
Mario A
MA
Ostrowski
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D016130:Immunophenotyping; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D054353:Perforin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000378:metabolism; D000098815:T-bet Transcription Factor
D000906:Antibodies; D018984:Epitopes, T-Lymphocyte; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D054353:Perforin