Selective inhibition of gelatinases modulates cellular energetics in CD4+ T-cells

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 affiliated with their activities in the extracellular milieu. However, recent studies have suggested that they contribute to normal intracellular function of various immune cell types, including T-cells. CD4+ T-cells play a key role in linking the innate and adaptive arms of the immune response, as well as determining the character of the immune response. Our findings show, for the first time, that intracellular gelatinase activity can modulate T-cell bioenergetics, affecting both oxidative phosphorylation and glycolytic pathways and resulting in a mitigated CD4+ T-cell response to stimulation. Upon stimulation, CD4+ T-cells lacking gelatinase activity demonstrate a reduced capacity to function 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 T-cell receptor signaling, cytokine production, and metabolism. These results suggest that gelatinases can be immunomodulatory agents in CD4+ T-cell mediated diseases, such as multiple sclerosis, and thus have therapeutic potential.