CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity.

Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.

How murine models of human disease and immunity are influenced by housing temperature and mild thermal stress.

At the direction of The Guide and Use of Laboratory Animals, rodents in laboratory facilities are housed at ambient temperatures between 20°C and 26°C, which fall below their thermoneutral zone (TNZ). TNZ is identified as a range of ambient temperatures that allow an organism to regulate body temperature without employing additional thermoregulatory processes (e.g. metabolic heat production driven by norepinephrine), thus leading to mild, chronic cold stress. For mice, this chronic cold stress leads to increased serum levels of the catecholamine norepinephrine, which has direct effects on various immune cells and several aspects of immunity and inflammation. Here, we review several studies that have revealed that ambient temperature significantly impacts outcomes in various murine models of human diseases, particularly those in which the immune system plays a major role in its pathogenesis. The impact of ambient temperature on experimental outcomes raises questions regarding the clinical relevance of some murine models of human disease, since studies examining rodents housed within thermoneutral ambient temperatures revealed that rodent disease pathology more closely resembled that of humans. Unlike laboratory rodents, humans can modify their surroundings accordingly - by adjusting their clothing, the thermostat, or their physical activity - to live within the appropriate TNZ, offering a possible explanation for why many studies using murine models of human disease conducted at thermoneutrality better represent patient outcomes. Thus, it is strongly recommended that ambient housing temperature in such studies be consistently and accurately reported and recognized as an important experimental variable.