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 3

TIGIT+ Tregs in the tumor tissue exhibit a more suppressive and activated phenotype.

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TIGIT+ Tregs in the tumor tissue exhibit a more suppressive and activate...
TIGIT+ and TIGIT– Tregs were isolated from B16F10 tumors implanted into Foxp3-GFP–KI mice (A, C, and D) or IL-10-Thy1.1 Foxp3-GFP–KI mice (B). (A) Gene expression was analyzed using a custom NanoString CodeSet. Bar graphs show the fold expression ± SEM of selected differentially expressed surface receptors (left), effector molecules, and transcription factors (TFs) (right) in TIGIT+ and TIGIT– Tregs. Data are pooled from 2 different experiments. Selected genes with a fold change of greater than 2 are depicted. (B) Left panels: representative flow cytometric data showing IL-10-Thy1.1 staining in TIGIT– and TIGIT+ Treg TILs. Right panel: frequency ± SEM of IL-10+ cells within TIGIT– and TIGIT+ Treg TILs (n = 5). Data are representative of 2 independent experiments. **P < 0.01 by Mann-Whitney U test. (C) Tregs isolated from tumor tissue were cocultured with splenic CT Violet–labeled CD4+ T cells (1:8). CT Violet dilution was analyzed by flow cytometry 4 days later. Gates indicate the undivided CD4+ subsets. Data are representative of 2 experiments. (D) Representative contour plots of TIM-3 expression on TIGIT+ TIL Tregs or TIGIT+ naive Tregs. Data are representative of 5 individual mice.