Novel role for gelatinases in modulating metabolic reprogramming associated with T cell receptor stimulation in CD4+ T cell

Abstract

Abstract The gelatinases, MMP-2 and MMP-9, are proteolytic enzymes with diverse physiological roles. They are linked with various aspects of the immune response, such as leukocyte trafficking and cytokine activation. However, their dysregulation is associated with various pathologies such as metastasis in cancer progression and blood-brain barrier disruption in multiple sclerosis. Much of what is known about the gelatinases is in context of their extracellular activities. However, recent studies including this study suggest an intracellular role in immune cell activation. Our findings suggest, that gelatinase activity can modulate T cell bioenergetics, affecting both oxidative phosphorylation and the glycolytic pathways with a greater influence on the latter. This results in a mitigated CD4+ T cell response to TCR stimulation. Upon stimulation, CD4+ T cells lacking gelatinase activity, demonstrate a reduced capacity to be activated as determined by the expression of early activation markers, proliferation, and the production of effector cytokines. In addition, RNA-seq analysis of control and gelatinase inhibited CD4+ T cells highlight key proteins associated with both the immune system and metabolic processes as predicted by STRING. We confirm our pharmacological studies with the genetic ablation of the gelatinases and further analysis of these shRNA treated T cells using the Nanostring metabolic panel. In addition, we demonstrate in-vivo relevancy using a murine model for multiple sclerosis known to be initiated by CD4+ T cells; gelatinase inhibition resulted in reduced clinical severity. These results suggest an intracellular role for gelatinases in CD4+ T cell mediated diseases and their potential as therapeutic targets.