Pulmonary resident effector CD4+ T cells fail to effectively utilize glycolysis

Abstract

Abstract The transition of T cells from naïve to effector cells has been reported to require a metabolic shift from oxidative phosphorylation to glycolysis for the production of effector molecules such as IFN-γ. This phenomenon is primarily restricted to study of splenic T cells and it is largely unknown if T cells in other organs undergo the same metabolic shift. Intranasal vaccination establishes a pool of lung tissue-resident, effector memory T cells (trTem) that are typically sufficient to control a secondary infection via production of cytokines. Therefore, we hypothesized trTem would be highly glycolytic upon activation. To test this hypothesis, we compared the metabolic activity of both trTem and circulating Tem (cTem) isolated from mice vaccinated with either Bordetella pertussis or Francisella tularensis. As expected, regardless of the vaccinating pathogen, CD4+ cTem readily shifted to glycolysis following activation with anti-CD3/CD28 beads. In contrast, CD4+ trTem cells did not shift to glycolysis following the same activation scheme, nor did they increase mitochondrial respiration as a mechanism to compensate for the absence of glycolysis. Consistent with an inability to shift to glycolysis, ex vivo stimulation of trTem with antigen also resulted in limited uptake of glucose as compared to cTem. These data suggested that, unlike previous reports, pulmonary CD4+ trTem do not rapidly shift to glycolysis even in the presence of antigen. Together these data highlight the unique environment of the pulmonary compartment and present critical information that will influence our understanding of pulmonary T cell responsiveness during infection which may shape future vaccination strategies.