TIGIT predominantly regulates the immune response via regulatory T cells

J Clin Invest. 2015 Nov 2;125(11):4053-62. doi: 10.1172/JCI81187. Epub 2015 Sep 28.

Abstract

Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Adoptive Transfer
  • Animals
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / pathology
  • DNA-Binding Proteins / deficiency
  • Female
  • Gene Expression Regulation, Neoplastic
  • Hepatitis A Virus Cellular Receptor 2
  • Immunophenotyping
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Receptors, Chemokine / biosynthesis
  • Receptors, Chemokine / genetics
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / physiology*
  • Receptors, Virus / biosynthesis
  • Receptors, Virus / genetics
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics

Substances

  • DNA-Binding Proteins
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Neoplasm Proteins
  • Rag2 protein, mouse
  • Receptors, Chemokine
  • Receptors, Immunologic
  • Receptors, Virus
  • T cell Ig and ITIM domain protein, mouse
  • Transcription Factors