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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Research Article Immunology

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 4

TIGIT restrains antitumor immune responses.

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TIGIT restrains antitumor immune responses. (A) Growth of B16F10 melanom...
(A) Growth of B16F10 melanoma or MC38 colon carcinoma in WT or Tigit–/– mice (n = 5–6). Data are representative of 3 independent experiments. ***P < 0.001 and ****P < 0.0001 by repeated-measures ANOVA with a Sidak test. (B) WT or Tigit–/– mice (n = 5) were treated i.p. with anti-asialoGM1 or anti-CD8β Abs or with their isotype controls (cIg) on days –1, 0, 7, and 14 after B16F10 tumor implantation. Tumor growth after anti-asialoGM1 (left) or anti-CD8β (right) treatment is shown. Data are representative of 2 independent experiments. Comparisons are between WT plus cIg versus Tigit–/–, irrespective of cIg or anti-asialoGM1 treatment (left), and between cIg versus anti-CD8β in Tigit–/– mice (right). ***P < 0.001 and ****P < 0.0001 by repeated-measures ANOVA with a Sidak test. (C and D) Total TILs were isolated from B16F10 tumor–bearing WT or Tigit–/– mice (n = 4–5). (C) TILs were stimulated with 10 μg/ml gp100 peptide. Contour plots and bar graphs show the percentage ± SEM of granzyme B+ cells and the normalized MFI of granzyme B expression within CD8+ TILs. MFI was normalized to the mean of WT CD8+ TILs in each independent experiment. Data were pooled from 2 to 3 experiments. *P < 0.05 and **P < 0.01 by Mann-Whitney U test. (D) CT Violet–labeled TILs were stimulated with anti-CD3 for 4 days and then analyzed by flow cytometry. Representative histogram of CT Violet dilution in CD8+ TILs. Data are representative of 3 individual measurements.