The Actin Regulatory Protein Hem1 Regulates T cell Homeostasis and Cytokine Production in a T Cell Specific Manner

Abstract

Hematopoietic Protein-1 (Hem1) is a hematopoietic cell specific component of the actin regulatory WAVE complex, which is activated downstream of multiple immune receptors and a mediator of f-actin polymerization. Mutations in the NCKAP1L gene encoding HEM1 have recently been found to result in severe Primary Immunodeficiency Disease (PID) in children. We utilized mouse models of constitutive and conditional deletion of Nckap1l to study the role Hem1 plays in T cell development, activation, and function. Hem1 deficient T cells exhibit ed a shift towards decreased naïve and increased memory T cells, and increased frequency of regulatory T cells. Loss of Hem1 specifically in T cells resulted in hallmarks of CD4 T cell exhaustion, including CD4 T cell lymphopenia, decreased activation and proliferation, increased expression of the inhibitory receptors PD-1 and Tim3, and increased IL-10 production. In vitro TCR stimulation of CD4 T cells resulted in significantly decreased expression of IL-2, and significantly increased production of the Th2 cytokines IL-4, IL-5, IL-13; increased Th17 cytokines IL-17, IL-22; and increased Treg cytokine IL-10. This correlated with decreased F-actin capping and increased expression of CD107a indicative of increased granule membrane fusion, suggesting increased release of cytokines secondary to cortical actin disruption. These results collectively suggest that Hem-1 and the WAVE Regulatory Complex (WRC) are critical for maintaining CD4 T cell homeostasis and regulated cytokine production following T cell activation.