Search

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T��cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T��cells, enhanced effectiveness of bi-specific T��cell engaging antibodies, and improved CAR T��cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T��cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.

CD8(+) T cells responding to chronic infection adapt an altered differentiation program that provides some restrain on pathogen replication yet limits immunopathology. This adaptation is imprinted in stem-like cells and propagated to their progeny. Understanding the molecular control of CD8(+) T cell differentiation in chronic infection has important therapeutic implications. Here, we found that the chemokine receptor CXCR3 was highly expressed on viral-specific stem-like CD8(+) T cells and that one of its ligands, CXCL10, regulated the persistence and heterogeneity of responding CD8(+) T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 was produced by inflammatory monocytes and fibroblasts of the splenic red pulp where it granted stem-like cells access to signals promoting differentiation and limited their exposure to pro-survival niches in the white pulp. Consequently, functional CD8(+) T cell responses were greater in Cxcl10(−/−) mice and were associated with a lower viral set point.

Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8

Naïve T cells and dendritic cells (DCs) are drawn to lymphoid tissue by the chemokine receptor CCR7, where its ligands CCL19 and CCL21 are secreted by lymphoid stroma. There, CCR7 fuels the fast migration of naïve T cells to expedite encounters with DCs presenting cognate pMHC, leading to the formation of long-lasting contacts. Direct in situ observations in mouse models have shown that after approximately 12–24 h, activated T cells detach from DCs before undergoing cell division and effector T cell differentiation. Yet, the mechanisms underlying T cell release from DCs, and hence termination of TCR signal integration, are not well understood. Using a reporter system for TCR signaling, we show here that CD8+T cell detachment from DCs does not occur efficiently in the absence of CCR7 ligands, suggesting that T cells do not intrinsically cease TCR signal integration. In contrast, after a short period of unresponsiveness, ex vivo stimulated T cells increasingly separate from DCs in response to CCR7 ligands in line with in vivo kinetics of detachment. Using ex vivo and in vivo imaging, we identify a critical role for phosphoinositide-3-kinase and the Rac activator DOCK2 in calibrating CCR7-dependent duration of T cell-DC interactions. To assess the impact of enforced T cell-DC separation, we examined effector differentiation kinetics as a function of interaction duration with DCs. Environmentally triggered CD8+T cell detachment from DCs positively correlated with their entry into proliferation and granzyme B production while limiting PD-1 expression. In sum, our data assign a novel function to CCR7 ligands secreted by lymphoid stroma to limit the duration of CD8+T cell - DC interactions for accelerated effector T cell generation.

How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8(+) T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8(+) T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8(+) T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8(+) T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8(+) T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness.

Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism and function during pathogen re-encounter remains unexplored. Here we show that at sites of infection, high acetate concentrations are being reached, yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite-acetate-induces distinct immunometabolic programs within the same cell type.