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Continual efferocytic clearance of apoptotic cells (ACs) by macrophages prevents necrosis and promotes injury resolution. How continual efferocytosis is promoted is not clear. Here,we show that the process is optimized by linking the metabolism of engulfed cargo from initial efferocytic events to subsequent rounds. We found that continual efferocytosis is enhanced by the metabolism of AC-derived arginine and ornithine to putrescine by macrophage arginase 1 (Arg1) and ornithine decarboxylase (ODC). Putrescine augments HuR-mediated stabilization of the mRNA encoding the GTP-exchange factor Dbl,which activates actin-regulating Rac1 to facilitate subsequent rounds of AC internalization. Inhibition of any step along this pathway after first-AC uptake suppresses second-AC internalization,whereas putrescine addition rescues this defect. Mice lacking myeloid Arg1 or ODC have defects in efferocytosis in vivo and in atherosclerosis regression,while treatment with putrescine promotes atherosclerosis resolution. Thus,macrophage metabolism of AC-derived metabolites allows for optimal continual efferocytosis and resolution of injury. View Publication

Spontaneous control of human immunodeficiency virus (HIV) is generally associated with an enhanced capacity of CD8+ T cells to eliminate infected CD4+ T cells,but the molecular characteristics of these highly functional CD8+ T cells are largely unknown. In the present study,using single-cell analysis,it was shown that HIV-specific,central memory CD8+ T cells from spontaneous HIV controllers (HICs) and antiretrovirally treated non-controllers have opposing transcriptomic profiles. Genes linked to effector functions and survival are upregulated in cells from HICs. In contrast,genes associated with activation,exhaustion and glycolysis are upregulated in cells from non-controllers. It was shown that HIV-specific CD8+ T cells from non-controllers are largely glucose dependent,whereas those from HICs have more diverse metabolic resources that enhance both their survival potential and their capacity to develop anti-HIV effector functions. The functional efficiency of the HIV-specific CD8+ T cell response in HICs is thus engraved in their memory population and related to their metabolic programme. Metabolic reprogramming in vitro through interleukin-15 treatment abrogated the glucose dependency and enhanced the antiviral potency of HIV-specific CD8+ T cells from non-controllers. View Publication

Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome,an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established,yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here,we report a non-conventional,T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2-/- CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous,Rip2-independent mechanism for Nod2 in uveitis. In naive animals,Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly,CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity,and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome. View Publication

Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2,such as TEPP-46 and DASA-58,limit tumorigenesis and inflammation. To understand how these compounds alter T cell function,we assessed their therapeutic activity in a mouse model of T cell-mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology,in part,through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17-producing TH17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition,we found that activation of PKM2 interfered with TGF-$\beta$1 signaling,which is necessary for the development of TH17 and regulatory T cells. Collectively,our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function. View Publication