The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse

Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim...

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Bibliographic Details
Published in:Science signaling 2021-06, Vol.14 (687)
Main Authors: Kataoka, Shunsuke, Manandhar, Priyanka, Lee, Judong, Workman, Creg J, Banerjee, Hridesh, Szymczak-Workman, Andrea L, Kvorjak, Michael, Lohmueller, Jason, Kane, Lawrence P
Format: Article
Language:English
Subjects:
AKT protein
Antigen-presenting cells
Antigens
Antitumor activity
Cell activation
Chimeric antigen receptors
Chronic infection
Costimulator
Domains
Downstream effects
Hepatitis A Virus Cellular Receptor 2 - genetics
Humans
Imaging techniques
Immunological Synapses
Localization
Lymphocyte Activation
Lymphocytes
Lymphocytes T
MAP kinase
MAP Kinase Signaling System
Persistent Infection
Phosphorylation
Proteins
Proto-Oncogene Proteins c-akt - genetics
Receptors
Recruitment
Ribosomal protein S6
Signaling
Solid tumors
Synapses
T cell receptors
Tumors
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Summary:Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3-mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the T cell immune synapse and its effects on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired the ability of Tim-3 to costimulate T cell receptor (TCR)-dependent S6 phosphorylation. Furthermore, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in a chimeric antigen receptor still enabled T cell activation. Together, our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.
ISSN:1945-0877
1937-9145
1937-9145
DOI:10.1126/scisignal.aba0717