TIGIT predominantly regulates the immune response via regulatory T cells
Sema Kurtulus, … , Vijay K. Kuchroo, Ana C. Anderson
Sema Kurtulus, … , Vijay K. Kuchroo, Ana C. Anderson
Published September 28, 2015
Citation Information: J Clin Invest. 2015;125(11):4053-4062. https://doi.org/10.1172/JCI81187.
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TIGIT predominantly regulates the immune response via regulatory T cells

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.

Authors

Sema Kurtulus, Kaori Sakuishi, Shin-Foong Ngiow, Nicole Joller, Dewar J. Tan, Michele W.L. Teng, Mark J. Smyth, Vijay K. Kuchroo, Ana C. Anderson

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Figure 7

TIM-3 and TIGIT synergize to suppress antitumor immunity.

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TIM-3 and TIGIT synergize to suppress antitumor immunity. (A) WT and Tig...
(A) WT and Tigit–/– mice (n = 5) were implanted s.c. with B16F10 melanoma cells and treated with 250 μg isotype or anti–TIM-3 (RMT3-23) Ab on days 3, 6, 9, and 12. Statistical comparisons are between WT plus Ig and Tigit–/– plus Ig and between Tigit–/– plus Ig and Tigit–/– plus anti–TIM-3. ****P < 0.0001 by repeated-measures ANOVA with a Sidak test. Data are representative of 2 experiments. (B and C) B16F10 melanoma cells or RM-1 cells were administered i.v. to WT mice (n = 5 per group) that were treated i.p. with 250 μg isotype (cIg) and/or anti–TIM-3 (RMT3-23) Ab on days 0 and 3. (B) Graphs show the number of foci ± SEM in the lungs after B16F10 (left) or RM-1 (right) cell injections on day 14. Statistical comparisons are between Tigit–/– plus cIg and Tigit–/– plus anti–TIM-3. **P < 0.01 by Mann-Whitney U test. Data are representative of 2 experiments. (C) Survival of mice (n = 10 per group) after i.v. administration of B16F10 melanoma cells. Statistical comparisons are between WT plus cIg and Tigit–/– plus cIg and between Tigit–/– plus cIg and Tigit–/– plus anti–TIM-3. ***P < 0.001 by log-rank test. Data were pooled from 2 independent experiments.