在移植社区,非常需要研究探索内源性替代品以诱导致耐受性的同种异体特异性免疫反应。在这方面,CD4+FoxP3+调节性T细胞(Tregs)由于其固有的天然免疫抑制特性而成为吸引人的候选者。迄今为止,已经阐明了决定Treg生存和健康的各种稳态因素,特别是抗原性CD3ζ/T细胞受体的非冗余作用,共刺激CD28和细胞因子白细胞介素(IL-)2依赖性信号传导。影响Tregs的许多其他生物信号仍有待阐明,然而,尤其是在移植方面。以前,我们在多发性骨髓瘤(MM)模型中证实了I型干扰素(IFN)和Treg之间的意外联系,在MM模型中,MM浆细胞通过增强I型IFN信号传导和诱导上调的Treg应答而逃避了免疫监视,这些上调的Treg应答可能被I型IFN信号特异性敲低所推翻.这里,我们通过评估I型IFN信号(IFN-α和-β)在同种免疫背景下对Treg稳态的作用来阐述这些发现。具体来说,我们研究了从初始CD4T细胞诱导Tregs。使用小鼠皮肤同种异体移植的体外和体内模型,我们发现I型IFN确实在时空上增强了初始CD4T细胞向FoxP3Tregs的极化。值得注意的是,然而,这种影响不是独立的,而是共同依赖,辅助细胞因子信号包括IL-2。这些发现为I型IFN途径在调节FoxP3+Treg反应中的相关性提供了证据,通过延伸,规定了通过I型IFN促进Treg健身的额外方法。
In the transplant community, research efforts exploring endogenous alternatives to inducing tolerogenic allo-specific immune responses are much needed. In this regard, CD4 + FoxP3+ regulatory T cells (Tregs) are appealing candidates due to their intrinsic natural immunosuppressive qualities. To date, various homeostatic factors that dictate Treg survival and fitness have been elucidated, particularly the non-redundant roles of antigenic CD3ζ/T-cell-receptor, co-stimulatory CD28, and cytokine interleukin (IL-)2 dependent signaling. Many of the additional biological signals that affect Tregs remain to be elucidated, however, especially in the transplant context. Previously, we demonstrated an unexpected link between type I interferons (IFNs) and Tregs in models of multiple myeloma (MM)-where MM plasmacytes escaped immunological surveillance by enhancing type I IFN signaling and precipitating upregulated Treg responses that could be overturned with specific knockdown of type I IFN signaling. Here, we elaborated on these findings by assessing the role of type I IFN signaling (IFN-α and -β) on Treg homeostasis within an alloimmune context. Specifically, we studied the induction of Tregs from naïve CD4 T cells. Using in vitro and in vivo models of murine skin allotransplantation, we found that type I IFN indeed spatiotemporally enhanced the polarization of naïve CD4 T cells into FoxP3+ Tregs. Notably, however, this effect was not independent of, and rather co-dependent on, ancillary cytokine signals including IL-2. These findings provide evidence for the relevance of type I IFN pathway in modulating FoxP3+ Treg responses and, by extension, stipulate an additional means of facilitating Treg fitness via type I IFNs.