Requirement of EHD family of endocytic recycling regulators for T-cell function.

Abstract

Abstract Regulatory mechanisms that ensure effective antigen-specific responses by T-cells without evoking autoimmune disease are of great interest in basic and clinical immunology. While signaling through T-cell receptor (TCR) and positive and negative co-receptors have received great attention, mechanisms that control the dynamic traffic of such receptors between the cell surface and intracellular compartments have received less attention. Based on the well-known ability of the TCR to undergo constitutive internalization and recycling to the cell surface, we hypothesized C-terminal Eps-15 Homology Domain-containing (EHD) proteins may play important roles in TCR-mediated T-cell functions by regulating the recycling of TCR and other receptors on T-cells. EHD proteins (EHD1-4) are key regulators of endocytic recycling of surface receptors, including the MHC-I and MHC-II proteins, but their role in TCR traffic or T-cell function is unknown. We found EHD1, 3 and 4 to be expressed in CD4+T cells. Accordingly, we generated a conditional knockout model in which floxed EHD1, 3 and 4 are deleted in CD4+T cells (CD4-Cre) of mice bearing a myelin oligodendrocyte glycoprotein (MOG)-specific TCR transgene. In vitro, CD4+T-cells from these mice exhibit reduced antigen-driven cell proliferation and IL-2 secretion. In vivo, these mice exhibit reduced severity of experimental autoimmune encephalomyelitis (EAE) upon immunization with antigen. Initial analyses suggest that the recycling of TCR (CD3ɛ) and the surface levels of TCR, CD28, LFA-1 and CD25 on the surface of CD4+ T cells are reduced by EHD1/3/4 knockout. Our studies reveal a novel role of the endocytic recycling proteins of the EHD family in TCR-mediated T-cell activation.