Nephrol Dial Transplant (2002) 17: 734-744
© 2002 European Renal Association-European Dialysis and Transplant Association
Chemoattraction of T cells expressing CCR5, CXCR3 and CX3CR1 by proximal tubular epithelial cell chemokines
1 Department of Nephrology, Queen Elizabeth Medical Centre and 2 Department of Renal Immunobiology, Division of Medical Sciences, Medical School, University of Birmingham, Birmingham, UK
Background. Chemokines produced by resident renal cells promote the infiltration of leukocyte subsets. We have analysed the chemotactic responses of CD3+ peripheral blood lymphocytes (PBLs) to factors secreted by proximal tubular epithelial cells (PTEC), assessing the role of chemokines and chemokine receptors in this process.
Methods. By FACS we analysed expression of the chemokine receptors CCR5, CXCR3, CX3CR1, CCR2, CXCR1 and CXCR2 on both freshly isolated and activated PBLs. Using Boyden chambers we studied the chemotactic activity of supernatant from resting and cytokine-stimulated (TNF-
and IFN-
) PTEC towards PBLs. Soluble recombinant chemokines and blocking antibodies were used to study the role of individual chemokine receptors. Chemokine secretion by PTEC was analysed by ELISA.
Results. Only a small proportion of freshly isolated cells expressed the chemokine receptors and there was low grade chemotaxis of these cells towards cytokine-stimulated PTEC supernatant compared with unstimulated PTEC supernatant. After activation, 84% of PBLs expressed CCR5, 90% expressed CXCR3 and 19% expressed CX3CR1. There remained low expression levels of CXCR1, CXCR2 and CCR2. Activated PBLs showed strong chemotactic responses to supernatant from cytokine-stimulated PTEC compared with unstimulated PTEC (P<0.001). Chemotaxis of these cells was inhibited by blocking CCR5, CXCR3 and CX3CR1 by 69%, 71% and 29% respectively, with complete inhibition following combined blockade. ELISA showed high levels of the chemokine RANTES/CCL5 (for CCR5) and IP-10/CXCL10 (for CXCR3) in cytokine-stimulated PTEC supernatant.
Conclusions. Chemokines produced by cytokine activated PTEC promote the selective recruitment of activated T cells via the receptors, CCR5, CXCR3 and CX3CR1. These receptors may be amenable to therapeutic manipulation in renal inflammation.
Keywords: CCR5; CXCR3; CX3CR1; chemokines; renal inflammation; proximal tubular epithelial cells; T cells
Correspondence and offprint requests to: Professor C. O. S. Savage, Renal Immunology Laboratory, Centre for Clinical Research in Immunology and Signalling (CCRIS), The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Email: C.O.S.Savage{at}bham.ac.uk
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