Abstract
Activation, recruitment, and effector function of T lymphocytes are essential for control of mycobacterial infection. These processes are tightly regulated in T cells by the availability of l-arginine within the microenvironment. In turn, mycobacterial infection dampens T cell responsiveness through arginase induction in myeloid cells, promoting sequestration of l-arginine within the local milieu. Here, we show T cells can replenish intracellular l-arginine through metabolism of l-citrulline to mediate inflammatory function, allowing anti-mycobacterial T cells to overcome arginase-mediated suppression. Furthermore, T cell l-citrulline metabolism is necessary for accumulation of CD4+ T cells at the site of infection, suggesting this metabolic pathway is involved during anti-mycobacterial T cell immunity in vivo. Together, these findings establish a contribution for l-arginine synthesis by T cells during mycobacterial infection, and implicate l-citrulline as a potential immuno-nutrient to modulate host immunity.
Highlights
Mycobacterium tuberculosis (Mtb) infection continues to plague global health, yet treatment and prevention methods targeting tuberculosis (TB) disease has generally remained stagnate in the last several decades
Lymphocytes were plated at 2 × 105 cells/well in R-free RPMI with 1 μg/ml α-CD3 supplemented with 1 mM l-arginine, 1 mM l-citrulline, or neither amino acid in the following polarizing conditions: TH1, anti-IL-4 and 10 ng/ml mouse recombinant IL-12 p70; TH2, anti-IL-12 p40, anti-IFN-γ, and 5 ng/ml mouse recombinant IL-4; TH17, anti-IL-4, anti-IFN-γ, 5 ng/ml mouse recombinant IL-6, 2.5 ng/ml recombinant IL-23, and 1.25 ng/ml recombinant TGF-β; regulatory T cell (Treg), anti-IFN-γ, 10 ng/ml TGF-β, and 10 ng/ml recombinant IL-2
Similar to our adoptive transfer data, AslΔTcell mice exhibited reduced frequency of CD4+ T cells in the mediastinal lymph nodes (mLNs), and reduced CD4+ T cell accumulation in the infected lung (Figures 6E–H), providing further evidence that l-citrulline metabolism supports T cell accumulation in relevant tissues following mycobacterial infection in vivo. These data reveal a role for the amino acid l-citrulline during anti-mycobacterial T cell responses
Summary
Mycobacterium tuberculosis (Mtb) infection continues to plague global health, yet treatment and prevention methods targeting tuberculosis (TB) disease has generally remained stagnate in the last several decades. During mycobacterial infection in mice, Arg activity suppresses T cell activity [20, 21] and correlates with decreased T cell responsiveness in TB patients [20], creating a metabolic hurdle for protective T cell immunity Despite this suppressive mechanism, T cells have acquired the ability to synthesize intrinsic l-arginine from the ubiquitous, non-canonical amino acid l-citrulline through the sequential activities of argininosuccinate synthase (Ass1) and argininosuccinate lyase (Asl) [22]. Our data reveal T cells rely on l-citrulline in microenvironments limited in l-arginine to maintain proliferation and cytokine production These in vitro observations led to the discovery that l-citrulline metabolism is required for local CD4+ T cell accumulation during mycobacterial infection in vivo
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