Al-Hamidi Abdulaziz, Pekalski Marcin, Robertson Helen, Ali Simi, Kirby John A
Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Mol Immunol. 2008 Sep;45(15):4000-7. doi: 10.1016/j.molimm.2008.06.011. Epub 2008 Jul 22.
Recruitment of activated T cells to the tubules is a defining feature of cell-mediated renal allograft rejection. Many of these intratubular T cells express the alphaE(CD103)beta7 integrin, potentially allowing adhesion to epithelial cells which express the only defined counter-receptor, E-cadherin. However, the potential of rejection-associated intratubular chemokines to modulate the adhesive function of this integrin has not been investigated. This study demonstrated that CCL7 is expressed within the tubules during renal allograft rejection. Modelling with CD103-expressing MOLT-16 T cells demonstrated chemotactic responses to the chemokines CXCL10, CXCL12, CCL5 and, most significantly, CCL7 (p<0.001); these responses were consistent with the expression of CXCR3, CXCR4 and CCR1 by these cells. A solid-phase adhesion assay showed little background binding of MOLT-16 cells to immobilised human E-cadherin.Fc fusion protein but alphaEbeta7 integrin-specific adhesion was greatly increased by the addition of either Mn2+ or 10nM CCL7 (p<0.01 or <0.001, respectively). Treatment of activated human peripheral T cells with TGFbeta1 for 3 days induced the expression of CD103 on a mean 53% of these cells; a similar proportion of CD103+ and CD103- T cells within these cultures expressed receptors for the chemokine CCL7. CD103+ T cell fractions were sorted from mitogen- or alloantigen-activated, TGFbeta1-treated T cell cultures and also showed specific enhancement of adhesion to E-cadherin.Fc fusion protein following stimulation with Mn2+ or 10nM CCL7 (p<0.01 in all cases); CD103- T cells were not adherent under any conditions. Together these data suggest that although the alphaEbeta7 integrin is induced on activated intratubular T cells by the presence of TGFbeta, the adhesive function of this integrin is promoted by the presence of chemokines such as CCL7, which are also expressed within tubules during renal allograft rejection.
活化T细胞向肾小管募集是细胞介导的肾移植排斥反应的一个决定性特征。许多肾小管内的T细胞表达αE（CD103）β7整合素，这可能使其与表达唯一已知配对受体E-钙黏蛋白的上皮细胞黏附。然而，与排斥反应相关的肾小管趋化因子对这种整合素黏附功能的调节作用尚未得到研究。本研究表明，CCL7在肾移植排斥反应期间在肾小管内表达。用表达CD103的MOLT-16 T细胞进行的模型实验表明，这些细胞对趋化因子CXCL10、CXCL12、CCL5以及最显著的CCL7有趋化反应（p<0.001）；这些反应与这些细胞表达CXCR3、CXCR4和CCR1一致。固相黏附实验显示MOLT-16细胞与固定化的人E-钙黏蛋白Fc融合蛋白的背景结合很少，但加入Mn2+或10nM CCL7后，αEβ7整合素特异性黏附显著增加（分别为p<0.01或<0.001）。用TGFβ1处理活化的人外周血T细胞3天，平均53%的细胞诱导表达CD103；这些培养物中相似比例的CD103+和CD103-T细胞表达趋化因子CCL7的受体。从经丝裂原或同种异体抗原激活、TGFβ1处理的T细胞培养物中分选CD103+ T细胞组分，在用Mn2+或10nM CCL7刺激后，其对E-钙黏蛋白Fc融合蛋白的黏附也有特异性增强（所有情况下p<0.01）；CD103-T细胞在任何条件下均无黏附。这些数据共同表明，虽然TGFβ的存在可诱导活化的肾小管内T细胞表达αEβ7整合素，但趋化因子如CCL7的存在可促进这种整合素的黏附功能，而CCL7在肾移植排斥反应期间也在肾小管内表达。
