TGFβ limits proximal CD8+ TCR signaling via PTPN22 following strong and moderate agonism.

Publication Title

Journal of immunology (Baltimore, Md. : 1950)

Authors

Andrew J Gunderson, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States.Follow
Kelley R Jordan, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States.Follow
Tomoko Yamazaki, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States.Follow
Hans-Peter Raué
Gwen Kramer, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States.Follow
Nathaniel E Fox, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States.Follow
Mark K Slifka
Michael J. Gough, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States.Follow
Marka R Crittenden, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States.; Radiation Oncology Division, The Oregon Clinic, Portland, OR, United States.Follow
Kristina H Young, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States.; Radiation Oncology Division, The Oregon Clinic, Portland, OR, United States.Follow

Document Type

Article

Publication Date

9-3-2025

Keywords

PTPN22; TCR signaling; TGFbeta; differentiation.; oregon; chiles

Abstract

Transforming growth factor beta (TGFβ) is an immunosuppressive cytokine that is overexpressed in tumor microenvironments. We have shown that CD8+ T cells with genetic ablation of the TGFβ type I receptor, Alk5 (CD8ΔALK5), were more sensitive to αCD3 stimulation resulting in enhanced proliferation and cytokine production. Based on these data, we hypothesized that TGFβ impaired T-cell receptor (TCR) signaling. We tested in vitro cytotoxicity of wild-type (WT) and CD8ΔALK5 OT-I T cells against murine oral carcinoma models transduced with ovalbumin altered peptide ligands (APLs) of differing affinities and found that loss of TGFβ renders CD8+ T cells more cytotoxic, but with diminishing effect at lower TCR agonism. TGFβ limits proximal TCR signaling intensity and duration, mediated by an interaction between the TGFβ type II receptor, PTPN22, and Zap70 that requires the Alk5 receptor. Downstream TCR signal integration is impaired by TGFβ following high and moderate, but not low TCR agonism. In vitro and in vivo models of chronic antigen stimulation demonstrate that TGFβ promotes both stem-like differentiation and terminal exhaustion, with loss of the more cytotoxic transitory exhausted population. Tumors of mixed APL clonality were implanted into Rag-/- animals followed by adoptive cell transfer of WT or CD8ΔALK5 OT-I T cells and monitored for clonal outgrowth. CD8ΔALK5 OT-I T cells were better able to control tumor clones with moderate TCR agonism compared to WT OT-I T cells. Targeting TGFβ signaling is one approach to enhance TCR signaling following strong or moderate agonism, alter differentiation toward more cytotoxic transitory exhaustion, and reduce terminal exhaustion, to improve antitumor immunity.

Area of Special Interest

Cancer

Specialty/Research Institute

Oncology

DOI

10.1093/jimmun/vkaf216