Abstract
IL-2 receptor (IL-2R) signaling is essential for optimal stability and function of CD4+CD25hiFOXP3+ regulatory T cells (Treg); a cell type that plays an integral role in maintaining tolerance. Thus, we hypothesized that decreased response to IL-2 may be a common phenotype of subjects who have autoimmune diseases associated with variants in the IL2RA locus, including T1D and MS, particularly in cells expressing the high affinity IL-2R alpha chain (IL-2RA or CD25). To examine this question we used phosphorylation of STAT5 (pSTAT5) as a downstream measure of IL-2R signaling, and found a decreased response to IL-2 in CD4+CD25hi T cells of T1D and MS, but not SLE patients. Since the IL2RArs2104286 haplotype is associated with T1D and MS, we measured pSTAT5 in controls carrying the rs2104286 risk haplotype to test whether this variant contributed to reduced IL-2 responsiveness. Consistent with this, we found decreased pSTAT5 in subjects carrying the rs2104286 risk haplotype. Reduced IL-2R signaling did not result from lower CD25 expression on CD25hi cells; instead we detected increased CD25 expression on naive Treg from controls carrying the rs2104286 risk haplotype, and subjects with T1D and MS. However the rs2104286 risk haplotype correlated with increased soluble IL-2RA levels, suggesting that shedding of the IL-2R may account in part for the reduced IL-2R signaling associated with the rs2104286 risk haplotype. In addition to risk variants in IL2RA, we found that the T1D-associated risk variant of PTPN2rs1893217 independently contributed to diminished IL-2R signaling. However, even when holding genotype constant at IL2RA and PTPN2, we still observed a significant signaling defect in T1D and MS patients. Together, these data suggest that multiple mechanisms converge in disease leading to decreased response to IL-2, a phenotype that may eventually lead to loss of tolerance and autoimmunity.
Highlights
The cytokine IL-2 is essential for T cell homeostasis
Consistent with previous studies, we found decreased response to IL-2 in the CD25lo population of type 1 diabetes (T1D) subjects ([11] and Figure 1B), we did not find this same decrease in the CD25lo cells of multiple sclerosis (MS) or SLE patients
Since IL-2 plays a key role in maintaining tolerance, it follows that patients with autoimmune diseases may display defects in the IL-2/IL-2 receptor (IL-2R) signaling pathway
Summary
Activated effector T cells (Teff) produce IL-2 and transiently up-regulate the high affinity IL-2RA (CD25) upon activation, enabling them to respond optimally to IL-2 following antigen encounter. In contrast to Teff, regulatory T cells (Treg) which are essential for suppressing autoimmunity do not produce IL-2 themselves, but paradoxically are highly dependent on IL-2 for their survival and function [4]. Treg constitutively express high levels of CD25 and are highly sensitive to even low doses of IL-2. The IL-2RB and common gamma chain can serve as a low affinity IL-2R. Upon cytokine binding the IL-2R, a series of sequential phosphorylation events are initiated from the beta and gamma chains including phosphorylation of JAK1, JAK3 and Shc proteins resulting in transcriptional activation of cytokine-targeted genes, including the STAT5-dependent Treg transcription factor FOXP3 and CD25 itself [5]
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