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- Title
Inhibition of T cell activation and function by the adaptor protein CIN85.
- Authors
Kong, Mei Suen; Hashimoto-Tane, Akiko; Kawashima, Yusuke; Sakuma, Machie; Yokosuka, Tadashi; Kometani, Kohei; Onishi, Reiko; Carpino, Nick; Ohara, Osamu; Kurosaki, Tomohiro; Phua, Kia Kien; Saito, Takashi
- Abstract
The adaptor CIN85 inhibits T cell activation through its association with the phosphatase Sts-2 after TCR stimulation. Thou shalt not CIN: The ubiquitously expressed adaptor protein CIN85 has distinct roles in different cell types. This adaptor inhibits the activation of the receptor tyrosine kinases EGFR and PDGFR but promotes B cell receptor signaling. To determine its function in T cells, Kong et al. compared the activation of mouse T cells lacking CIN85 or the highly related adaptor CD2AP. Only loss of CIN85 augmented T cell growth and IL-2 production. CIN85 associated with the inhibitory phosphatase Sts-2 and promoted its recruitment to T cell receptor microclusters after activation. These data define a previously unknown inhibitory interaction, which could be targeted to augment T cell function in cancer and immunity. T cell activation is initiated by signaling molecules downstream of the T cell receptor (TCR) that are organized by adaptor proteins. CIN85 (Cbl-interacting protein of 85 kDa) is one such adaptor protein. Here, we showed that CIN85 limited T cell responses to TCR stimulation. Compared to activated wild-type (WT) T cells, those that lacked CIN85 produced more IL-2 and exhibited greater proliferation. After stimulation of WT T cells with their cognate antigen, CIN85 was recruited to the TCR signaling complex. Early TCR signaling events, such as phosphorylation of ζ-chain–associated protein kinase 70 (Zap70), Src homology 2 (SH2) domain–containing leukocyte protein of 76 kDa (SLP76), and extracellular signal–regulated kinase (Erk), were enhanced in CIN85-deficient T cells. The inhibitory function of CIN85 required the SH3 and PR regions of the adaptor, which associated with the phosphatase suppressor of TCR signaling–2 (Sts-2) after TCR stimulation. Together, our data suggest that CIN85 is recruited to the TCR signaling complex and mediates inhibition of T cell activation through its association with Sts-2.
- Subjects
T cells; PHOSPHATASES; ADAPTOR proteins; PROTEIN-tyrosine kinases; IMMUNITY
- Publication
Science Signaling, 2019, Vol 12, Issue 567, pN.PAG
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aav4373