Graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplants (aHSCTs). Pre-HSCT chemoradiation results in the death of dividing cells and release of endogenous danger signals. These molecules drive the activation of antigen presenting cells (APCs) and the differentiation of allo-reactive donor T cells. We identified a role for Stimulator of Interferon Genes (STING), an innate immune sensor, in GVHD using pre-clinical MHC-matched unrelated donor (MUD) HSCT models. Here we show that STING rapidly promotes donor CD8⁺ T cell activation and recipient APC death early after aHSCT.

Post MUD HSCT, we previously found a >2x reduction in IFNβ, TNFα and IL-6 mRNA in STING^−/− vs WT recipient colonic mRNA expression (48 hrs) as well as decreased weight loss, GVHD scores and skin pathology (6 wks) vs WT. Chimeric studies showed that STING loss in non-hematopoietic cells induced this effect. Conversely, we recently found a single early (<D14), but not late (>D100), dose of the STING agonist DMXAA increased GVHD scores and lethality in WT, but not STING^−/−, recipients. Thus, the activation of this pathway can promote GVHD following MUD HSCT. Furthermore, mice homozygous for a murine homologue of a human allele associated with diminished STING activity (STING^HAQ/HAQ) also exhibited reduced GVHD after MUD HSCT, suggesting potential clinical importance.

Interestingly, our findings that STING deficiency ameliorates GVHD in MUD HSCT (Bader CS, et al, in revision Sci. Transl. Med.) contrasts reported observations that STING deficiency can exacerbate GVHD after MHC-mismatched (MMUD) HSCT. Since CD4⁺ and CD8⁺ T cells are central in MMUD and MUD GVHD, respectively, we transplanted MMUD BALB/c BM + CD8⁺ T cells into B6-WT and STING^−/− mice and notably, found that STING^−/- recipients now developed reduced GVHD clinical scores, skin pathology and frequencies of activated T cells 8 wks post-HSCT vs WT. We also found that STING^−/− mice had greater numbers of recipient splenic CD11b⁺CD11c⁺ APCs and these cells expressed reduced MHC I protein 1 day after MMUD B6 into BALB/c aHSCT vs WT (Fig. A, B). Moreover, STING^−/− recipient spleens contained lower numbers of donor CD8⁺ T cells producing IFNγ and TNFα (Fig. C), supporting the hypothesis that STING contributes to early activation of donor CD8⁺ T cells and loss of recipient APCs. Next, to identify if reduced host MHC II⁺ APCs affected donor CD4⁺ T cell activation, B6-Nur77^GFP T cells were used to explicitly monitor T cell receptor signaling. Indeed, STING^−/− spleens had greater numbers of donor Nur77^GFP CD4⁺ T cells expressing GFP, CD69 and IFNγ 6 days post-HSCT (Fig. D). Overall, these data provide a mechanism by which STING could promote CD8⁺ T cell-mediated GVHD yet diminish CD4⁺-mediated GVHD. Ongoing studies are exploring the use of STING agonists to augment GVL following aHSCT.

移植物抗宿主病（GVHD）仍然是接受异基因造血干细胞移植（aHSCT）的患者发病和死亡的重要原因。HSCT之前的化学放射会导致分裂细胞死亡并释放内源性危险信号。这些分子驱动抗原呈递细胞（APC）的激活和同种反应性供体T细胞的分化。我们使用临床前MHC匹配的无关供体（MUD）HSCT模型在GVHD中确定了先天性免疫传感器干扰素基因刺激（STING）的作用。在这里，我们显示STING在aHSCT早期迅速促进供体CD8 ⁺ T细胞活化和受体APC死亡。

在MUD HSCT之后，我们先前发现STING ^-/-相对于WT受体结肠mRNA表达（48小时）的IFNβ，TNFα和IL-6 mRNA降低了> 2倍，并且体重减轻，GVHD评分和皮肤病理学降低（6周） ）与WT。嵌合研究表明，非造血细胞中STING的缺失会诱导这种效应。相反，我们最近发现，单剂量的STING激动剂DMXAA早期（<D14），但没有晚期（> D100），增加了WT接受者的GVHD评分和致死率，但没有增加STING ^-/-的接受者。因此，该途径的激活可以促进MUD HSCT后的GVHD。此外，与人类等位基因的鼠同源物纯合的小鼠与STING活性降低有关（STING ^{HAQ / HAQ}）在MUD HSCT后也表现出GVHD降低，表明潜在的临床重要性。

有趣的是，我们的发现STING缺乏症改善了MUD HSCT中的GVHD（Bader CS等，修订版Sci。Transl。Med。），与此相反，据报道，观察到STING缺乏症会在MHC不匹配（MMUD）HSCT之后加重GVHD。由于CD4 ⁺和CD8 ⁺ T细胞分别位于MMUD和MUD GVHD的中心，我们将MMUD BALB / c BM + CD8 ⁺ T细胞移植到B6-WT和STING ^-/-小鼠中，尤其是发现STING ^-/-受体HSCT与WT后8周，GVHD的临床评分，皮肤病理学和活化T细胞频率降低，现已被开发出来。我们还发现STING ^-/-小鼠脾脏CD11b ⁺ CD11c的数量更多⁺ APC和这些细胞在MMUD B6进入BALB / c aHSCT与WT后1天表达降低的MHC I蛋白（图A，B）。此外，STING ^-/-受体脾脏中含有较少数量的产生IFNγ和TNFα的供体CD8 ⁺ T细胞（图C），支持以下假设：STING有助于供体CD8 ⁺ T细胞的早期活化和受体APC的丧失。接下来，为了确定减少的宿主MHC II ⁺ APC是否影响供体CD4 ⁺ T细胞活化，使用B6-Nur77 ^GFP T细胞显式监测T细胞受体信号传导。确实，STING ^-/-脾脏具有更多数量的供体Nur77 ^GFP CD4 ⁺HSCT后6天表达GFP，CD69和IFNγ的T细胞（图D）。总体而言，这些数据提供了一种机制，通过该机制，STING可以促进CD8 ⁺ T细胞介导的GVHD而又减少CD4 ⁺介导的GVHD。正在进行的研究正在探索在aHSCT之后使用STING激动剂来增加GVL。