Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 11, Pages 4053-4062Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI81187
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Funding
- American Cancer Society [RSG-11-057-01-LIB]
- Melanoma Research Foundation
- Career Development Award from the Brigham and Women's Hospital
- NIH [P01AI073748, R01NS045937, P01AI039671]
- National Health and Medical Research Council (NHMRC) [1078671, 1093566]
- QIMR Berghofer Medical Research Institute Rio Tinto Ride to Conquer Cancer Grant
- NHMRC
- National Health and Medical Research Council of Australia [1093566] Funding Source: NHMRC
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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.
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