Chronic viral infection is often associated with the dysfunction of virus-specific T cells. Our studies using Il21r-deficient (Il21r-/-) mice now suggest that interleukin-21 (IL-21) is critical for the long-term maintenance and functionality of CD8+ T cells and the control of chronic lymphocytic choriomeningitis virus infection in mice. Cell-autonomous IL-21 receptor (IL-21R)-dependent signaling by CD8+ T cells was required for sustained cell proliferation and cytokine production during chronic infection. Il21r-/- mice showed normal CD8+ T cell expansion, effector function, memory homeostasis, and recall responses during acute and after resolved infection with several other nonpersistent viruses. These data suggest that IL-21R signaling is required for the maintenance of polyfunctional T cells during chronic viral infections and have implications for understanding the immune response to other persisting antigens, such as tumors.

Matsushita et al. investigated the role of the selenoenzyme glutathione peroxidae 4 (Gpx4) in T cell responses and found that loss of Gpx4 results in an intrinsic T cell developmental defect in the periphery, which leads to a failure to expand and protect from acute viral and parasitic infection.The defects were rescued with dietary supplementation of vitamin E. The Gp4−/− T cells accumulate membrane lipid peroxides and undergo cell death by ferroptosis.

Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8 + T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-α production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.

Chronic inflammation is a fundamental aspect of metabolic disorders such as obesity, diabetes and cardiovascular disease. Cholesterol crystals are metabolic signals that trigger sterile inflammation in atherosclerosis, presumably by activating inflammasomes for IL-1β production. We found here that atherogenesis was mediated by IL-1α and we identified fatty acids as potent inducers of IL-1α-driven vascular inflammation. Fatty acids selectively stimulated the release of IL-1α but not of IL-1β by uncoupling mitochondrial respiration. Fatty acid-induced mitochondrial uncoupling abrogated IL-1β secretion, which deviated the cholesterol crystal-elicited response toward selective production of IL-1α. Our findings delineate a previously unknown pathway for vascular immunopathology that links the cellular response to metabolic stress with innate inflammation, and suggest that IL-1α, not IL-1β, should be targeted in patients with cardiovascular disease.