High distribution of CD40 and TRAF2 in Th40 T cell rafts lead to preferential survival of this auto-aggressive population in autoimmunity

Abstract

Background: CD40-CD154 interactions have proven critical in autoimmunity, with the indentification of CD4loCD40+ T cells (Th40 cells) as harboring an autoaggressive T cell population shedding new insights into those disease processes. Th40 cells are present at contained levels in non-autoimmune individuals but are significantly expanded in autoimmunity. Th40 cells in T cells and whether there are differences in that signaling and subsequent outcome depending on disease conditions. When CD40 is engaged, CD40 and TNF-receptor associated factors. TRAFs, become associated with lipid raft microdomains. Dysregulation of T cell homeostasis is emerging as a major contributor to autoimmune disease and thwarted apoptosis is key in breaking homeostasis. Methodology/Principal Findings: Cells were sorted into CD4hi and CD40lo (Th40 cells) then treated and assayed either as whole or fractionated cells lysates. Protein expression was assayed by western blot and Nf-κB DNA-binding activity by electrophoretic mobility shifts. We demonstrate here that autoimmune NOD Th40 cells have drastically exaggerated expression of CD40 on a pre-cell basis compared to non-autoimmune BALB/c. Immediately ex vivo, untreated Th40 cells from NOD mice have high levels of CD40 and TRAF2 associated with the raft microdomain while Th40 cells from NOR and BALB/c mice do not. CD40 engagement of Th40 cells induces Nf-κB DNA-binding activity and anti-apoptotic Bcl-XL expression in all three mouse strains. However, only in NOD Th40 cells is anti-apoptotic cFLIPp43 induced which leads to preferential survival and proliferation. Importantly, CD40 engagement recues NOD Th40 cells from FAs-induced death. Conclusion/Significance: CD40 may act as a switch between life and death promoting signals and NOD Th40 cells are poised for survival via this switch. This may explain how they expand in autoimmunity to thwart T cell homeostasis. © 2008 Vaitaitis, Wagner Jr.