CEACAM1 regulates TIM-3-mediated tolerance and exhaustion
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 cancers1, 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 inhibition6, 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.
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F1000 Microbiology
University of Tennessee, Knoxville, TN, USA.
NEW FINDING
DOI: 10.3410/f.725223775.793501268
An increasing number of disease circumstances appear to be the consequence of poorly performing (often called exhausted) T cells. Fortunately, poor performance is correctable if the mechanisms responsible are blunted, but all of the players involved are yet to be identified. The present paper by Blumberg and colleagues adds further mechanistic understanding of underachieving T cells. It shows that the molecule TIM-3, already advocated as involved in mediating exhaustion, is controlled by a second molecule CEACAM-1 formerly linked to T cell regulation {1}. The new results show that TIM-3 expression and its inhibitory function are controlled by interacting with CEACAM-1. Moreover, the co-blockage of both molecules was more effective in delaying tumor growth in a mouse model of colorectal cancer than could be achieved by blocking TIM-3 alone. Already, there is clinical evidence that co-blockade of PD-1 and CTLA-4 is useful to control some tumors. It could be that additionally manipulating the CEACAM-1/TIM-3 interaction might provide an even more effective means of resurrecting T cell poor performance.
References
1.Activation-induced expression of carcinoembryonic antigen-cell adhesion molecule 1 regulates mouse T lymphocyte function.
Nakajima A, Iijima H, Neurath MF, Nagaishi T, Nieuwenhuis EE, Raychowdhury R, Glickman J, Blau DM, Russell S, Holmes KV, Blumberg RS. J Immunol 2002 Feb 1; 168(3):1028-35
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