Lina Taslima T, Gonzalez Jazmin, Pinchuk Irina V, Beswick Ellen J, Reyes Victor E
Department of Pediatrics, University of Texas Medical Branch.
Division of Gastroenterology and Hepatology, Penn State Cancer Institute.
Clin Oncol Res. 2019;2(5). doi: 10.31487/j.cor.2019.05.05. Epub 2019 Oct 10.
() is a gram negative bacterium that infects more than 50% of humanity and is associated with gastritis, peptic ulcer and gastric cancer. Although CD4 T cells are recruited to the gastric mucosa, the host is unable to clear the bacteria. Previously, we demonstrated that infection upregulates the expression of the T cell co-inhibitory molecule B7-H1 while simultaneously downregulating the expression of T cell co-stimulatory molecule B7-H2 on gastric epithelial cells (GEC), which together affect the Treg and Th17 cell balance and foster bacterial persistence. Because B7-H3, another member of the B7 family of co-inhibitory receptors, has been found to have important immunoregulatory roles and in cancer, in this study we examined the expression of B7-H3 molecules on GEC and how the expression is regulated by during infection. Our study showed that both human and murine GEC constitutively express B7-H3 molecules, but their expression levels increased during infection. We further demonstrated that uses its type 4 secretion system (T4SS) components CagA and cell wall peptidoglycan (PG) fragment to upregulate B7-H3. Th17 cells and Treg cells which are increased during infection also had an effect on B7-H3 induction. The underlying cell signaling pathway involves modulation of p38MAPK pathway. Since B7-H3 were shown to up-regulate Th2 responses, the phenotype of T cell subpopulations in mice infected with PMSS1 or SS1 strains were characterized. A mixed Th1/Th2 response in infected mice was observed. Consistent with previous findings, increased Treg cells and decreased Th17 cells in MLN of PMSS1 infected mice compared to SS1 infected mice was observed. Human biopsy samples collected from gastritis biopsies and gastric tumors showed a strong association between increased B7-H3 and Th2 responses in strains associated with gastritis. T cell: GEC co-cultures and anti-B7-H3 blocking Ab confirmed that the induction of Th2 is mediated by B7-H3 and associated exclusively with an gastritis strain not cancer or ulcer strains. In conclusion, these studies revealed a novel regulatory mechanism employed by to influence the type of T cell response that develops within the infected gastric mucosa.
（）是一种革兰氏阴性菌，感染了超过50%的人类，并与胃炎、消化性溃疡和胃癌相关。尽管CD4 T细胞被募集到胃黏膜，但宿主无法清除这种细菌。此前，我们证明感染会上调胃上皮细胞（GEC）上T细胞共抑制分子B7-H1的表达，同时下调T细胞共刺激分子B7-H2的表达，这共同影响调节性T细胞（Treg）和辅助性T细胞17（Th17）细胞的平衡并促进细菌持续存在。由于共抑制受体B7家族的另一个成员B7-H3已被发现具有重要的免疫调节作用且在癌症中也有作用，在本研究中，我们检测了GEC上B7-H3分子的表达以及在感染期间其表达如何受到调控。我们的研究表明，人和小鼠的GEC都组成性表达B7-H3分子，但在感染期间其表达水平升高。我们进一步证明利用其4型分泌系统（T4SS）成分CagA和细胞壁肽聚糖（PG）片段上调B7-H3。在感染期间增加的Th17细胞和Treg细胞也对B7-H3的诱导有影响。潜在的细胞信号通路涉及p38丝裂原活化蛋白激酶（p38MAPK）通路的调节。由于B7-H3被证明可上调Th2反应，对感染PMSS1或SS1菌株的小鼠中T细胞亚群的表型进行了表征。观察到感染小鼠中有混合的Th1/Th2反应。与先前的发现一致，与感染SS1的小鼠相比，感染PMSS1的小鼠肠系膜淋巴结（MLN）中Treg细胞增加而Th17细胞减少。从胃炎活检和胃肿瘤收集的人类活检样本显示，在与胃炎相关的菌株中，B7-H3增加与Th2反应之间存在强烈关联。T细胞：GEC共培养和抗B7-H3阻断抗体证实，Th2的诱导由B7-H3介导，且仅与胃炎菌株相关，而非癌症或溃疡菌株。总之，这些研究揭示了用来影响感染的胃黏膜内发展的T细胞反应类型的一种新的调节机制。
