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PDBsum entry 4qxw
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Cell adhesion
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PDB id
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4qxw
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References listed in PDB file
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Key reference
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Title
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Ceacam1 regulates tim-3-Mediated tolerance and exhaustion.
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Authors
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Y.H.Huang,
C.Zhu,
Y.Kondo,
A.C.Anderson,
A.Gandhi,
A.Russell,
S.K.Dougan,
B.S.Petersen,
E.Melum,
T.Pertel,
K.L.Clayton,
M.Raab,
Q.Chen,
N.Beauchemin,
P.J.Yazaki,
M.Pyzik,
M.A.Ostrowski,
J.N.Glickman,
C.E.Rudd,
H.L.Ploegh,
A.Franke,
G.A.Petsko,
V.K.Kuchroo,
R.S.Blumberg.
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Ref.
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Nature, 2015,
517,
386-390.
[DOI no: ]
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PubMed id
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Abstract
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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. 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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