Intrinsic and extrinsic regulation of antiviral T cell responses by MMP2

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

Investigators

Abstract

PROJECT SUMMARY The research proposed in this application aims to identify the cellular mechanisms by which matrix metalloprotease (MMP) 2 regulates antiviral T cell immunity. Influenza viruses are very contagious and cause significant morbidity and mortality in yearly epidemics that affect the elderly disproportionally. T cell responses at the nasal and pulmonary mucosa are crucial in resolving viral infection and protecting from future challenges. Here, we demonstrate the novel finding that MMP2 is absolutely required for CD4+ and CD8+ T cell immunity. MMPs are a family of proteolytic enzymes that perform important biological functions, but while their contribution to infectious disease is being recognized, their specific function and mode of action in immune cells remains to be fully elucidated. Our preliminary data highlight a substantial, but complex, role for MMP2 in the regulation of T cell responses. We demonstrate that T cell-derived MMP2 functions in a cell- intrinsic fashion regulating the proliferative capacity of antiviral CD8+ T cells. Interestingly, our results show that in addition to this intrinsic MMP2 requirement, there are also T cell-extrinsic components by which MMP2 indirectly regulates T cell immunity in vivo. While we have identified substantial roles for a hematopoietic and a stromal cell subset, the identity of the specific cell subsets and the functional mechanisms by which they contribute to the T cell response remain unknown. This application aims to generate the tools to identify the cellular and molecular mechanisms by which MMP2 regulates antiviral T cell immunity. We will develop floxed mmp2 mice to enable the conditional or inducible genetic ablation of MMP2 in specific hematopoietic and stromal cell subsets and we will investigate the cellular mechanisms by which extrinsic MMP2 affects T cell biology in vivo. The identification of the mechanisms underlying the mode of action of MMP2 as a crucial regulator of T cell immunity will further our basic knowledge of T cell biology, but will also have substantial therapeutic implications.