Phosphatases in T cell regulation during autoimmunity and anti-cancer responses

Tyrosine phosphatases play critical roles in regulation of immunity, but the molecular mechanisms are poorly understood. Shp1 and Shp2 tyrosine phosphatases are highly expressed in T cells, but their molecular functions have not yet been fully elucidated. We have recently developed a conditional knockout mouse model with T cell lineage-specific deletion of Shp1 and Shp2, or the individual phosphatases. We discovered that the double phosphatase deficiency resulted in an increase in CD4+CD25+ regulatory T cells (Tregs) and the recently described CD8+CD44hiLy49+ Tregs, suggesting redundant roles of Shp1 and Shp2 in Treg development. We aim to determine the molecular roles of Shp1 and Shp2 phosphatases in development and function of Tregs. We will elucidate the molecular basis of Shp1 and Shp2-dependent control of Treg development. We will determine if the increase in CD4+ Tregs is due to enhanced IL2 and/or TCR signal during thymic development, or enhanced TGFβ signal in mature T cells. As almost nothing is known about CD8+ Treg development, we will identify CD8+ Treg precursors using bone marrow cultures, adoptive transfers and single cell RNAseq analysis, testing if Shp1 and Shp2 modulate CD8+ Tregs by augmenting IL15 signals. We will determine if Shp1 and Shp2 phosphatases control CD4+ Treg and CD8+ Treg suppressive functions in autoimmunity and cancer, using mouse models of multiple sclerosis and melanoma, respectively. We will elucidate the molecular basis of Shp1 and Shp2-dependent control of CD4+ and CD8+ Treg suppression, focusing on T cell receptor and cytokine signals, as well as signals from the inhibitory receptors PD1 and Ly49 in Tregs. We will also use pharmacological inhibition of Shp1 and Shp2 phosphatase activity to validate findings from the mouse systems in human T cells, and to test the translational potential of modulating Shp1 and Shp2 phosphatase activity to control human T cell suppression.