CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adenoassociated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions. rAAV | CTL | TCR | cytotoxicity T he liver is acknowledged to possess unique tolerogenic properties, which have likely evolved to maintain immunological unresponsiveness toward food-derived and microbial antigens that enter the circulation via the gut (1, 2). This tolerogenic capability of the liver is demonstrated in animal models of liver transplantation, in which liver allografts are accepted across complete MHC mismatch barriers and are able to protect other donor tissues from rejection (reviewed in ref.3). In humans, the tolerogenic hepatic environment is likely to contribute to impaired immune clearance of the hepatitis B virus (HBV) and hepatitis C virus (HCV), which result in persistent infection in a significant proportion of exposed individuals and are associated with major morbidity and mortality. In contrast, effective immune responses to hepatotropic pathogens leading to resolution of infection are observed in most hepatitis A and E virus infections, the majority of individuals infected with HBV during adulthood, and a minority of those infected by HCV (reviewed in refs. 4, 5). The liver is also susceptible to a variety of autoimmune-mediated conditions (6). Collectively, these observations indicate that effective immune responses can be initiated and/or sustained in the liver despite its apparent predisposition toward the generation of tolerance. Unfortunately, there is no small animal model in which to study the parameters that determine the balance between intrahepatic immunity and tolerance in viral hepatitis. Thus, the factors that shape immune outcome have not yet been identified.By studying the fate of ...

Obesity underpins the development of numerous chronic diseases, such as type II diabetes mellitus. It is well established that obesity negatively alters immune cell frequencies and functions. Mucosal-associated invariant T (MAIT) cells are a population of innate T cells, which we have previously reported are dysregulated in obesity, with altered circulating and adipose tissue frequencies and a reduction in their IFN-g production, which is a critical effector function of MAIT cells in host defense. Hence, there is increased urgency to characterize the key molecular mechanisms that drive MAIT cell effector functions and to identify those which are impaired in the obesity setting. In this study, we found that MAIT cells significantly upregulate their rates of glycolysis upon activation in an mTORC1-dependent manner, and this is essential for MAIT cell IFN-g production. Furthermore, we show that mTORC1 activation is dependent on amino acid transport via SLC7A5. In obese patients, using RNA sequencing, Seahorse analysis, and a series of in vitro experiments, we demonstrate that MAIT cells isolated from obese adults display defective glycolytic metabolism, mTORC1 signaling, and SLC7A5 aa transport. Collectively, our data detail the intrinsic metabolic pathways controlling MAIT cell cytokine production and highlight mTORC1 as an important metabolic regulator that is impaired in obesity, leading to altered MAIT cell responses.