Renal allograft rejection: the contribution of chemokines to the adhesion and retention of alphaE(CD103)beta7 integrin-expressing intratubular T cells.

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.