Regulation of systemic autoimmunity and CD11c+ Tbet+ B cells by SWEF proteins

Abstract

Recent studies have revealed the existence of a T-bet dependent subset of B cells, which expresses unique phenotypic and functional characteristics including high levels of CD11c and CD11b. In the murine system this B cell subset has been termed Age/autoimmune-associated B cells (ABCs) since it expands with age in non-autoimmune mice and it prematurely accumulates in autoimmune-prone strains. The molecular mechanisms that promote the expansion and function of ABCs are largely unknown. This review will focus on the SWEF proteins, a small family of Rho GEFs comprised of SWAP-70 and its homolog DEF6, a newly identified risk variant for human SLE. We will first provide an overview of the SWEF proteins and then discuss the complex array of biological processes that they control and the autoimmune phenotypes that spontaneously develop in their absence, highlighting the emerging involvement of these proteins in regulating ABCs. A better understanding of the pathways controlled by the SWEF proteins could help provide new insights into the mechanisms responsible for the expansion of ABCs in autoimmunity and potentially guide the design of novel therapeutic approaches.

Keywords: Age-associated B cells; Autoimmunity; DEF6; SWAP-70.

Figure 1. Diagram of DEF6 and SWAP-70

DEF6 and SWAP-70 are highly homologous and are comprised of an N-terminal domain, which contains a putative EF hand, a central Pleckstrin Homology (PH) domain, and a C-terminal domain termed DH-like. Y: Tyrosine residues.

Figure 2. DEF6 localization and function

A) TCR engagement leads to the tyrosine phosphorylation of the N-terminal region of DEF6 by Lck, resulting in a conformational change, which enables the relocalization of DEF6 to the immunological synapse where DEF6 can promote the activation of Rac and Cdc42 via its DHL domain. B) In the nucleus DEF6 regulates IRF4 function by sequestering IRF4 and by inhibiting IRF4 phosphorylation by the serine-threonine kinase, ROCK2. C) DEF6 inhibits the assembly of the p62-TRAF6-Raptor tri-molecular complex by directly interacting with p62 and TRAF6 thus controlling the ability of mTORC1 to regulate the translation of a specific group of proteins.