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 domai...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3390352?pdf=render |
| _version_ | 1811260236908986368 |
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| author | Ali Sakhdari Shariq Mujib Bahareh Vali Feng Yun Yue Sonya MacParland Kiera Clayton Richard Bradley Jones Jun Liu Erika Yue Lee Erika Benko Colin Kovacs Jennifer Gommerman Rupert Kaul Mario A Ostrowski |
| author_facet | Ali Sakhdari Shariq Mujib Bahareh Vali Feng Yun Yue Sonya MacParland Kiera Clayton Richard Bradley Jones Jun Liu Erika Yue Lee Erika Benko Colin Kovacs Jennifer Gommerman Rupert Kaul Mario A Ostrowski |
| author_sort | Ali Sakhdari |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T18:44:20Z |
| format | Article |
| id | doaj.art-76d8c9b63d264921a05910338fce7ddb |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T18:44:20Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-76d8c9b63d264921a05910338fce7ddb2022-12-22T03:20:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0177e4014610.1371/journal.pone.0040146Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection.Ali SakhdariShariq MujibBahareh ValiFeng Yun YueSonya MacParlandKiera ClaytonRichard Bradley JonesJun LiuErika Yue LeeErika BenkoColin KovacsJennifer GommermanRupert KaulMario A OstrowskiCytotoxic 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.http://europepmc.org/articles/PMC3390352?pdf=render |
| spellingShingle | Ali Sakhdari Shariq Mujib Bahareh Vali Feng Yun Yue Sonya MacParland Kiera Clayton Richard Bradley Jones Jun Liu Erika Yue Lee Erika Benko Colin Kovacs Jennifer Gommerman Rupert Kaul Mario A Ostrowski Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection. PLoS ONE |
| title | Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection. |
| title_full | Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection. |
| title_fullStr | Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection. |
| title_full_unstemmed | Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection. |
| title_short | Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection. |
| title_sort | tim 3 negatively regulates cytotoxicity in exhausted cd8 t cells in hiv infection |
| url | http://europepmc.org/articles/PMC3390352?pdf=render |
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