Dendritic Cells Supply CD4+ T Cells With L-arginine

Abstract

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis, is responsible for over 1 million deaths each year. Mycobacteria-infected dendritic cells (DCs) migrate to the lymph node to initiate adaptive immune priming, which is vital to antimycobacterial immunity. This response is intimately tied to nutrient availability – especially the amino acid L-arginine (L-ARG), metabolism of which is altered in TB patients. We have characterized a pathway utilized by immune cells to synthesize L-ARG. Loss of L-ARG synthesis in CD11c+ cells, which includes DCs, results in increased mycobacterial burden following infection in mice. To characterize the role of this pathway in DCs, we developed a co-culture system with mycobacterial-specific CD4+ T cells and bone marrow derived DCs. Using CD4+ T cells and DCs with differing capabilities of L-ARG synthesis, we found 1) DC L-ARG synthesis supports CD4+ T cell proliferation and 2) activated T cells contain DC-derived L-ARG. We hypothesize DCs “share” synthesized L-ARG to support CD4+ T cell activation when L-ARG is limiting. Our data suggest nutrient availability as a 4th signal – following antigen presentation, co-stimulation, and cytokine receptor ligation – required for T cell activation. This work expands the current model of DC-T cell interactions and provides insight into the effects of nutrient availability in immune cells.