Abstract
BackgroundCD40–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 FindingsCells 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-κB 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 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 rescues NOD Th40 cells from Fas-induced death.Conclusions/SignificanceCD40 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.
Highlights
The role of CD40–CD154 interactions in autoimmune diseases [1,2] including type I diabetes (T1D) [3,4,5], collagen induced arthritis [6,7], systemic lupus erythamotosis [8,9], and autoimmune thyroiditis [10], has been well documented
Because we demonstrated a causal relationship of CD40–CD154 interactions leading to expansion of potentially autoaggressive Th40 cells in vivo [4], we investigated whether CD40-signals directly to the T cell can be responsible for such an expansion
Given that nonobese diabetic (NOD) Th40 cells readily survive in response to CD40 engagement we examined whether there were differences in Bcl-XL and cFLIP expression between Th40 cells from NOD, NOR and BALB/c mice
Summary
The role of CD40–CD154 interactions in autoimmune diseases [1,2] including type I diabetes (T1D) [3,4,5], collagen induced arthritis [6,7], systemic lupus erythamotosis [8,9], and autoimmune thyroiditis [10], has been well documented. CD40 (tnfrsf5) belongs to the TNF-receptor family and when CD40 is engaged it becomes associated with lipid rafts to interact with the adaptor molecules, TNF receptor associated factors (TRAFs), for downstream signaling [11]. Do differences exist in the signaling outcome between autoimmune and non-autoimmune conditions? The Th40 cell subset is greatly expanded under autoimmune conditions and is necessary and sufficient in diabetes transfers from the nonobese diabetic (NOD) mouse to NOD.scid animals [4,15,16]. Little is known about CD40 signaling in T cells and whether there are differences in that signaling and subsequent outcome depending on disease conditions. Dysregulation of T cell homeostasis is emerging as a major contributor to autoimmune disease and thwarted apoptosis is key in breaking homeostasis
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