Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion.
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Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion. / Rangachari, Manu; Zhu, Chen; Sakuishi, Kaori; Xiao, Sheng; Karman, Jozsef; Chen, Andrew; Angin, Mathieu; Wakeham, Andrew; Greenfield, Edward A; Sobel, Raymond A; Okada, Hitoshi; McKinnon, Peter J; Mak, Tak W; Addo, Marylyn; Anderson, Ana C; Kuchroo, Vijay K.
In: NAT MED, Vol. 18, No. 9, 9, 2012, p. 1394-1400.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion.
AU - Rangachari, Manu
AU - Zhu, Chen
AU - Sakuishi, Kaori
AU - Xiao, Sheng
AU - Karman, Jozsef
AU - Chen, Andrew
AU - Angin, Mathieu
AU - Wakeham, Andrew
AU - Greenfield, Edward A
AU - Sobel, Raymond A
AU - Okada, Hitoshi
AU - McKinnon, Peter J
AU - Mak, Tak W
AU - Addo, Marylyn
AU - Anderson, Ana C
AU - Kuchroo, Vijay K
PY - 2012
Y1 - 2012
N2 - T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (TH1) cells from galectin-9–mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigen–specific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon-? (IFN-?)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1–infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3–dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.
AB - T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (TH1) cells from galectin-9–mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigen–specific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon-? (IFN-?)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1–infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3–dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - Flow Cytometry
KW - Statistics, Nonparametric
KW - Transduction, Genetic
KW - HEK293 Cells
KW - Genetic Vectors
KW - Real-Time Polymerase Chain Reaction
KW - Membrane Proteins/metabolism
KW - DNA-Binding Proteins/genetics
KW - Transcription Factors/genetics
KW - Autoimmunity/immunology
KW - Cell Death/immunology
KW - Homeodomain Proteins/genetics
KW - Molecular Chaperones/genetics/immunology/metabolism
KW - Retroviridae
KW - T-Lymphocytes/immunology/metabolism
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - Flow Cytometry
KW - Statistics, Nonparametric
KW - Transduction, Genetic
KW - HEK293 Cells
KW - Genetic Vectors
KW - Real-Time Polymerase Chain Reaction
KW - Membrane Proteins/metabolism
KW - DNA-Binding Proteins/genetics
KW - Transcription Factors/genetics
KW - Autoimmunity/immunology
KW - Cell Death/immunology
KW - Homeodomain Proteins/genetics
KW - Molecular Chaperones/genetics/immunology/metabolism
KW - Retroviridae
KW - T-Lymphocytes/immunology/metabolism
M3 - SCORING: Journal article
VL - 18
SP - 1394
EP - 1400
JO - NAT MED
JF - NAT MED
SN - 1078-8956
IS - 9
M1 - 9
ER -