CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.
CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.
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DOI：
10.1038/nature13848
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发表时间：
2015-01-15
期刊：
影响因子：
64.8
通讯作者：
Blumberg, Richard S.
中科院分区：
文献类型：
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作者：
Huang, Yu-Hwa;Zhu, Chen;Kondo, Yasuyuki;Anderson, Ana C.;Gandhi, Amit;Russell, Andrew;Dougan, Stephanie K.;Petersen, Britt-Sabina;Melum, Espen;Pertel, Thomas;Clayton, Kiera L.;Raab, Monika;Chen, Qiang;Beauchemin, Nicole;Yazaki, Paul J.;Pyzik, Michal;Ostrowski, Mario A.;Glickman, Jonathan N.;Rudd, Christopher E.;Ploegh, Hidde L.;Franke, Andre;Petsko, Gregory A.;Kuchroo, Vijay K.;Blumberg, Richard S.
T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.
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影响因子：
32.4
作者：
Chen L;Chen Z;Baker K;Halvorsen EM;da Cunha AP;Flak MB;Gerber G;Huang YH;Hosomi S;Arthur JC;Dery KJ;Nagaishi T;Beauchemin N;Holmes KV;Ho JW;Shively JE;Jobin C;Onderdonk AB;Bry L;Weiner HL;Higgins DE;Blumberg RS
通讯作者：
Blumberg RS
影响因子：
2.9
作者：
Kaufmann, Kristian W.;Lemmon, Gordon H.;DeLuca, Samuel L.;Sheehan, Jonathan H.;Meiler, Jens
通讯作者：
Meiler, Jens
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.4
作者：
Gallagher, TM
通讯作者：
Gallagher, TM
影响因子：
64.8
作者：
通讯作者：
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