TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments

Yuan-Li Tsai; Marcel Arias-Badia; Theresa A Kadlecek; Yee May Lwin; Aahir Srinath; Neel H Shah; Zhi-En Wang; Diane Barber; John Kuriyan; Lawrence Fong; Arthur Weiss

doi:10.1016/j.immuni.2023.11.010

TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments

Immunity. 2023 Dec 12;56(12):2682-2698.e9. doi: 10.1016/j.immuni.2023.11.010.

Authors

Affiliations

¹ Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
² Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Chemistry, Columbia University, New York, NY 10027, USA.
⁴ Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁷ Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].

Abstract

T cell responses are inhibited by acidic environments. T cell receptor (TCR)-induced protein phosphorylation is negatively regulated by dephosphorylation and/or ubiquitination, but the mechanisms underlying sensitivity to acidic environments are not fully understood. Here, we found that TCR stimulation induced a molecular complex of Cbl-b, an E3-ubiquitin ligase, with STS1, a pH-sensitive unconventional phosphatase. The induced interaction depended upon a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1 dephosphorylated Cbl-b interacting phosphoproteins. The deficiency of STS1 or Cbl-b diminished the sensitivity of T cell responses to the inhibitory effects of acid in an autocrine or paracrine manner in vitro or in vivo. Moreover, the deficiency of STS1 or Cbl-b promoted T cell proliferative and differentiation activities in vivo and inhibited tumor growth, prolonged survival, and improved T cell fitness in tumor models. Thus, a TCR-induced STS1-Cbl-b complex senses intra- or extra-cellular acidity and regulates T cell responses, presenting a potential therapeutic target for improving anti-tumor immunity.

Keywords: TCR signaling; pH sensing; phosphatase.

MeSH terms

Hydrogen-Ion Concentration
Phosphoric Monoester Hydrolases / metabolism
Receptors, Antigen, T-Cell / metabolism
Signal Transduction*
T-Lymphocytes*
Ubiquitin-Protein Ligases / metabolism

Substances

Ubiquitin-Protein Ligases
Receptors, Antigen, T-Cell
Phosphoric Monoester Hydrolases

Abstract

MeSH terms

Substances

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