Immunology

Highlights

 

•NFAT proteins induce a transcriptional program of CD8+ T cell exhaustion•CD8+ T cells lacking NFAT fail to express inhibitory surface receptors•An engineered NFAT that cannot cooperate with AP-1 strongly induces exhaustion•The engineered NFAT1 blunts TCR signaling and impairs CD8+ function in vivo

 

Summary

During persistent antigen stimulation, CD8+ T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of T cell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished T cell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8+ T cells to protect against Listeriainfection and attenuate tumor growth in vivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8+ T cells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8+ T cells in vivo. Our data show that NFAT promotes T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1.

Via Krishan Maggon

Thymocytes and mature T cells are exposed to a broad range of self-peptides of varying reactivity with TCRs. Hogquist and Jameson discuss how differences in self-reactivity and TCR signal strength dictate subsequent cell fates.

 

Self-reactivity was once seen as a potential characteristic of T cells that was eliminated by clonal selection to protect the host from autoimmune pathology. It is now understood that the T cell repertoire is in fact broadly self-reactive, even self-centered. The strength with which a T cell reacts to self ligands and the environmental context in which this reaction occurs influence almost every aspect of T cell biology, from development to differentiation to effector function. Here we highlight recent advances and discoveries that relate to T cell self-reactivity, with a particular emphasis on T cell antigen receptor (TCR) signaling thresholds.

Via Krishan Maggon

RT @genentech: New paper from our scientists in @Cancer_Cell shows how TIGIT may be potential #immunotherapy target http://t.co/FswC0GF9YB

 

Highlights

 

•Human and murine tumor-infiltrating CD8+ T cells express high levels of TIGIT•Antibody coblockade of TIGIT and PDL1 elicits tumor rejection in preclinical models•TIGIT selectively limits the effector function of chronically stimulated CD8+T cells•TIGIT interacts with CD226 in cis and disrupts CD226 homodimerization

 

Summary

Tumors constitute highly suppressive microenvironments in which infiltrating T cells are “exhausted” by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8+ T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8+ T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT’s complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8+ T cell-dependent responses.

Via Krishan Maggon

How agonist peptides initiate the T cell antigen receptor (TCR) signaling cascade is widely debated. Weiss and Chakraborty discuss current models of the proximal signaling events that ensue upon recognition of agonist peptide-MHC complexes by TCRs.

 

The initiation of T cell antigen receptor signaling is a key step that can result in T cell activation and the orchestration of an adaptive immune response. Early events in T cell receptor signaling can distinguish between agonist and endogenous ligands with exquisite selectivity, and show extraordinary sensitivity to minute numbers of agonists in a sea of endogenous ligands. We review our current knowledge of models and crucial molecules that aim to provide a mechanistic explanation for these observations. Building on current understanding and a discussion of unresolved issues, we propose a molecular model for initiation of T cell receptor signaling that may serve as a useful guide for future studies.

Via Krishan Maggon