high distribution of cd40 and traf2 in th40 t cell rafts leads to preferential survival of this auto-aggressive population in autoimmunity高分布的cd40和traf2在th40 t细胞木筏导致优惠这auto-aggressive人口自身免疫的生存.pdfVIP

High Distribution of CD40 and TRAF2 in Th40 T Cell Rafts Leads to Preferential Survival of this Auto-Aggressive Population in Autoimmunity Gisela M. Vaitaitis, David H. Wagner Jr.* The Department of Medicine and Webb-Waring Institute, University of Colorado Denver, Denver, Colorado, United States of America Abstract Background: CD40–CD154 interactions have proven critical in autoimmunity, with the identification 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 are necessary and sufficient in transferring type 1 diabetes in mouse models. However, little is known about CD40 signaling 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 CD4lo (Th40 cells) then treated and assayed either as whole or fractionated cell lysates. Protein expression was assayed by western blot and Nf-kB DNA-binding activity by electrophoretic mobility shifts. We demonstrate here that autoimmune NOD Th40 cells have drastically exaggerated expression of CD40 on a per-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 induc