TIGIT regulates apoptosis of risky memory T cell subsets implicated in belatacept-resistant rejection

He Sun, Christina R. Hartigan, Ching wen Chen, Yini Sun, Marvi Tariq, Jennifer M. Robertson, Scott M. Krummey, Aneesh K. Mehta, Mandy L. Ford

Research output: Contribution to journalArticlepeer-review

Abstract

Belatacept confers increased patient and graft survival in renal transplant recipients relative to calcineurin inhibitors, but is associated with an increased rate of acute rejection. Recent immunophenotypic studies comparing pretransplant T cell phenotypes of patients who reject versus those who remain stable on belatacept identified three potential “risky” memory T cell subsets that potentially underlie belatacept-resistant rejection: CD4+ CD28+ TEM, CD8+ CD28null, and CD4+ CD57+ PD1 subsets. Here, we compared key phenotypic and functional aspects of these human memory T cell subsets, with the goal of identifying additional potential targets to modulate them. Results demonstrate that TIGIT, an increasingly well-appreciated immune checkpoint receptor, was expressed on all three risky memory T cell subsets in vitro and in vivo in the presence of belatacept. Coculture of human memory CD4+ and CD8+ T cells with an agonistic anti-TIGIT mAb significantly increased apoptotic cell death of all three risky memory T cell subsets. Mechanistically, TIGIT-mediated apoptosis of risky memory T cells was dependent on FOXP3+ Treg, suggesting that agonism of the TIGIT pathway increases FOXP3+ Treg suppression of human memory T cell populations. Overall, these data suggest that TIGIT agonism could represent a new therapeutic target to inhibit belatacept-resistant rejection during transplantation.

Original languageEnglish (US)
JournalAmerican Journal of Transplantation
DOIs
StateAccepted/In press - 2021
Externally publishedYes

Keywords

  • basic (laboratory) research/science
  • cell death: apoptosis
  • cellular biology
  • costimulation
  • immune regulation
  • T cell biology

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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