CEACAM1 regulates TIM-3-mediated tolerance and exhaustion
Author(s)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.; Franke, Andre; Petsko, Gregory A.; Kuchroo, Vijay K.; Blumberg, Richard S.; Ploegh, Hidde; ... Show more Show less
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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[superscript 1, 2, 3, 4, 5]. 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[superscript 6, 7, 8, 9, 10]. 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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
Nature Publishing Group
Huang, Yu-Hwa, Chen Zhu, Yasuyuki Kondo, Ana C. Anderson, Amit Gandhi, Andrew Russell, Stephanie K. Dougan, et al. “CEACAM1 Regulates TIM-3-Mediated Tolerance and Exhaustion.” Nature 517, no. 7534 (October 26, 2014): 386–390.
Author's final manuscript