Adaptor SLP-76 couples the TCR to glucose metabolism in T-cells with augmented obesity 2310033

Abstract Introduction The adaptor protein SLP-76 is indispensable for thymic T-cell development, yet its contribution to peripheral T-cell signaling and metabolic programming remains poorly defined. T-cell receptor (TCR) engagement rapidly induces a glycolytic switch that supports effector differentiation, but the TCR-proximal signaling mechanisms initiating this metabolic reprogramming are unknown. Methods Here, we generated a knock-in mouse expressing a single point mutation in SLP-76 (K56E) that permits normal thymic development and maintains a numerically intact peripheral CD4+ and CD8+ T-cell compartment. Results Despite preserved T-cell numbers, K56E T cells exhibited markedly impaired effector function, including reduced interferon-γ production and defective CD8+ cytolytic activity. Integrated transcriptomic, metabolomic, and bioenergetic analyses revealed a selective failure of glycolytic commitment, with diminished 13C-glucose flux through glycolysis and the tricarboxylic acid cycle. These data identify SLP-76 as a critical signaling node linking TCR engagement glycolytic metabolic reprogramming. At the organismal level, K56E mice displayed a spontaneous Th2 bias and accelerated weight gain on a standard low-fat diet, a phenotype exacerbated under high-fat feeding. Immune profiling revealed increased M1 macrophages and effector CD8+ T cells, accompanied by reduced γδ T cells and NK cells in fat tissue. Conclusion Together, these findings uncover SLP-76 as a previously unrecognized upstream regulator of glycolytic programming and weight gain that governs CD8+ T-cell effector fate and systemic immunometabolic homeostasis, with implications for tumor immunity. Funding Source Canadian institute of health research Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)