Abstract
Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance.
Highlights
Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology
We found that TIGIT is highly expressed during the course of chronic LCMV clone 13 infection on both CD4+ and CD8+ T cells as well as on Tregs (Fig. 1a–c, h), the latter displaying the highest expression of TIGIT throughout the course of infection
We asked whether TIGIT was upregulated on antigen-specific T cells that are known to become exhausted during chronic viral infections
Summary
Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. Immunemodulatory cytokines like IL-10 play an important role in disease progression during chronic infection, as it has been shown that polymorphisms in IL-10 or IL10RA are associated with increased susceptibility to chronic HCV and HBV infection[6,7] Many of these characteristics are shared by dysfunctional T cells that arise during the development of cancer, and targeting co-inhibitory receptors has emerged as a potent immune-modulatory strategy in order to “revitalize” the antitumor response for the treatment of such conditions. As TIGIT ligation is functionally linked to IL-10 expression that is known to both promote virus persistence in vivo, and limit adverse immunopathological damage, the TIGIT pathway might represent an important regulatory gatekeeper for the control of viral infections. TIGIT blockade or stimulation alone is not sufficient to promote virus clearance or persistence but rather plays an important role in limiting immune pathology in peripheral organs in an IL-10-dependent manner
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