T time for ADAR: ADAR1 is required for T cell self-tolerance

Abstract

ADAR1, an RNA‐editing enzyme, plays a key role in preventing self‐RNAs from triggering autoinflammatory responses. In this issue of EMBO reports, Nakahama and colleagues uncover a novel role for ADAR1 in T cells 1. The authors report that in T cells, ADAR1‐mediated suppression of type I interferon‐stimulated gene (ISG) expression is required for thymic T cell self‐tolerance and prevention of colitis. These findings establish a novel function of ADAR1 in T cells and suggest that autoreactive T cells may contribute to disease symptoms in autoinflammatory disorders.

Figure 1. ADAR1 is required for thymic T cell maturation and intestinal homeostasis

(A) Schematic of ADAR1's role in thymic T cells. In brief, ADAR1 is postulated to prevent endogenous double‐stranded RNAs (dsRNAs) from activating MDA5, a PRR for viral dsRNA. In ADAR1‐deficient thymocytes, MDA5 activation leads to excessive ISG expression and defective T cell receptor (TCR) signaling. As a result, ADAR1‐deficient thymocytes are impaired in positive and negative selection. Positive selection occurs when TCRs “moderately” bind to self‐peptide/MHC (major histocompatibility complex) complexes. Following positive selection, negative selection removes T cells with TCRs that “strongly” bind to self‐peptide/MHC complexes. Negative selection is an essential step to delete autoreactive T cells. APC, antigen presenting cell. (B) While wild‐type (WT) mice are healthy, mice with ADAR1‐deficient T cells spontaneously develop colitis. Colitis is likely caused by the impaired T cell maturation described in (A).