Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions.
T-cell immune responses modulated by T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) during Mycobacterium tuberculosis (Mtb) infection in humans remain poorly understood. Here, we found that active TB patients exhibited increases in numbers of Tim-3-expressing CD4(+) and CD8(+)...
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1002984&type=printable |
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| author | Yueqin Qiu Jianbo Chen Hongying Liao Yan Zhang Hua Wang Shaoyuan Li Yanfen Luo Danyun Fang Guobao Li Boping Zhou Ling Shen Crystal Y Chen Dan Huang Jiye Cai Kaiyuan Cao Lifang Jiang Gucheng Zeng Zheng W Chen |
| author_facet | Yueqin Qiu Jianbo Chen Hongying Liao Yan Zhang Hua Wang Shaoyuan Li Yanfen Luo Danyun Fang Guobao Li Boping Zhou Ling Shen Crystal Y Chen Dan Huang Jiye Cai Kaiyuan Cao Lifang Jiang Gucheng Zeng Zheng W Chen |
| author_sort | Yueqin Qiu |
| collection | DOAJ |
| description | T-cell immune responses modulated by T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) during Mycobacterium tuberculosis (Mtb) infection in humans remain poorly understood. Here, we found that active TB patients exhibited increases in numbers of Tim-3-expressing CD4(+) and CD8(+) T cells, which preferentially displayed polarized effector memory phenotypes. Consistent with effector phenotypes, Tim-3(+)CD4(+) and Tim-3(+)CD8(+) T-cell subsets showed greater effector functions for producing Th1/Th22 cytokines and CTL effector molecules than Tim-3(-) counterparts, and Tim-3-expressing T cells more apparently limited intracellular Mtb replication in macrophages. The increased effector functions for Tim-3-expressing T cells consisted with cellular activation signaling as Tim-3(+)CD4(+) and Tim-3(+)CD8(+) T-cell subsets expressed much higher levels of phosphorylated signaling molecules p38, stat3, stat5, and Erk1/2 than Tim-3- controls. Mechanistic experiments showed that siRNA silencing of Tim-3 or soluble Tim-3 treatment interfering with membrane Tim-3-ligand interaction reduced de novo production of IFN-γ and TNF-α by Tim-3-expressing T cells. Furthermore, stimulation of Tim-3 signaling pathways by antibody cross-linking of membrane Tim-3 augmented effector function of IFN-γ production by CD4(+) and CD8(+) T cells, suggesting that Tim-3 signaling helped to drive stronger effector functions in active TB patients. This study therefore uncovered a previously unknown mechanism for T-cell immune responses regulated by Tim-3, and findings may have implications for potential immune intervention in TB. |
| format | Article |
| id | doaj-art-d6a5e5bde6ea480085f0b43c4f4feff4 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-d6a5e5bde6ea480085f0b43c4f4feff42025-08-20T02:15:19ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742012-01-01811e100298410.1371/journal.ppat.1002984Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions.Yueqin QiuJianbo ChenHongying LiaoYan ZhangHua WangShaoyuan LiYanfen LuoDanyun FangGuobao LiBoping ZhouLing ShenCrystal Y ChenDan HuangJiye CaiKaiyuan CaoLifang JiangGucheng ZengZheng W ChenT-cell immune responses modulated by T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) during Mycobacterium tuberculosis (Mtb) infection in humans remain poorly understood. Here, we found that active TB patients exhibited increases in numbers of Tim-3-expressing CD4(+) and CD8(+) T cells, which preferentially displayed polarized effector memory phenotypes. Consistent with effector phenotypes, Tim-3(+)CD4(+) and Tim-3(+)CD8(+) T-cell subsets showed greater effector functions for producing Th1/Th22 cytokines and CTL effector molecules than Tim-3(-) counterparts, and Tim-3-expressing T cells more apparently limited intracellular Mtb replication in macrophages. The increased effector functions for Tim-3-expressing T cells consisted with cellular activation signaling as Tim-3(+)CD4(+) and Tim-3(+)CD8(+) T-cell subsets expressed much higher levels of phosphorylated signaling molecules p38, stat3, stat5, and Erk1/2 than Tim-3- controls. Mechanistic experiments showed that siRNA silencing of Tim-3 or soluble Tim-3 treatment interfering with membrane Tim-3-ligand interaction reduced de novo production of IFN-γ and TNF-α by Tim-3-expressing T cells. Furthermore, stimulation of Tim-3 signaling pathways by antibody cross-linking of membrane Tim-3 augmented effector function of IFN-γ production by CD4(+) and CD8(+) T cells, suggesting that Tim-3 signaling helped to drive stronger effector functions in active TB patients. This study therefore uncovered a previously unknown mechanism for T-cell immune responses regulated by Tim-3, and findings may have implications for potential immune intervention in TB.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1002984&type=printable |
| spellingShingle | Yueqin Qiu Jianbo Chen Hongying Liao Yan Zhang Hua Wang Shaoyuan Li Yanfen Luo Danyun Fang Guobao Li Boping Zhou Ling Shen Crystal Y Chen Dan Huang Jiye Cai Kaiyuan Cao Lifang Jiang Gucheng Zeng Zheng W Chen Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. PLoS Pathogens |
| title | Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. |
| title_full | Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. |
| title_fullStr | Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. |
| title_full_unstemmed | Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. |
| title_short | Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. |
| title_sort | tim 3 expressing cd4 and cd8 t cells in human tuberculosis tb exhibit polarized effector memory phenotypes and stronger anti tb effector functions |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1002984&type=printable |
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