Amino acids are important nutrients integral to the function of T cells ? key cells necessary for optimal immune activity during infection, vaccination, and anti-tumor immunity, to name a few. Harnessing amino acid metabo- lism to regulate T cell function, therefore, is an intriguing and exciting avenue of research. Still, fundamental gaps in the field include 1) understanding intercellular communication driven by amino acids, and 2) determin- ing immune cell intrinsic necessities of amino acid acquisition. The applicant?s long-term goal is to define the interplay between amino acid metabolism and basic immune responses, providing new therapeutic avenues to manipulate immune activity. The objective of this study is to 1) identify how L-arginine acquisition and utiliza- tion is regulated in T cell / antigen presenting cell interactions when L-arginine synthesis is ablated in one, or both, cell populations, and 2) determine the T cell-intrinsic necessity of L-arginine synthesis when rescuing immune-deficient mice in a mycobacteria-infection model. The applicant?s laboratory will draw on their exper- tise in defining the contribution of L-arginine metabolism during virulent and attenuated mycobacterial infection. Specifically, the applicant has generated TCR-transgenic mice specific for the dominant Ag85b mycobacterial antigen that are unable to synthesize L-arginine from L-citrulline to test how T cell L-arginine synthesis regu- lates immune function in the context of mycobacterial stimulation (in vitro) or infection (in vivo). The central hypothesis is that antigen presenting cells provide synthesized L-arginine to CD4+ T cells, enabling their ex- pansion and effector function. The applicant will test the hypothesis in two related, but independent aims.
In Aim 1, the applicant will address two questions: 1) how does L-arginine synthesis in antigen presenting cells impact T cell proliferation and cytokine production, and 2) can L-arginine synthesized from L-citrulline be found within CD4+ T cells intrinsically deficient in generating L-arginine? In Aim 2, the applicant will address if T cell- intrinsic L-arginine synthesis is necessary for host immunity to mycobacteria in vivo. The proposed research is significant and is expected to lead towards a better understanding of 1) amino acid mediated regulation of lym- phocyte function and 2) communication pathways vital to T cell / antigen presenting cell interactions, potentially exposing new avenues of host-directed therapy within, and outside the realm of host defense against infection. Uncovering the impact of ?immunonutrition? is expected to advance the overall missions of the NIAID and NIH by seeking fundamental knowledge to understand and prevent infectious disease, providing new directions to enhance health and reduce illness.
Harnessing metabolic pathways to regulate cellular responses is promising, yet inadequate information exists on the basic necessities of many metabolites ? including amino acids ? in biological microenvironments. The proposed research aims to explore how nutrient acquisition and utilization (i.e. L-arginine metabolism and synthesis) fundamentally dictates T cell function. This research is relevant to public health because regulating T cell activity by targeting amino acid metabolism may lead to improved host defense, immunization strategies, and/or decreasing autoimmune activity.
