title: Complement activation regulates the capacity of proximal tubular epithelial cell to stimulate alloreactive T cell response.
abstract: Tissue expression of C3 is an unexpected regulator of the alloimmune response in mouse kidney transplantation. It is unclear, however, whether a direct or an indirect action of complement on the host immune response is involved. Also unknown is which of the complement effector products, cleaved C3, cleaved C5, or C5b-9, is responsible. Proximal tubular epithelial cells (PTEC) not only constitute a major target of the alloimmune response but also produce substantial amounts of C3. This study investigated the property of mouse PTEC to stimulate alloreactive T cells in a complement-dependent manner. The proliferative and cytokine responses of primed alloreactive T cells were measured after exposure to donor-specific PTEC that had been pretreated with normal mouse serum, heat-inactivated mouse serum, or complement- deficient (C3, C5, or C6) mouse sera to differentially deposit complement components. PTEC were able to stimulate alloreactive T cells in an antigen-specific manner. Complement activation leading to the deposition of cleaved C3 on PTEC enhanced the alloreactive T cell response. This complement-mediated stimulation of the T cell response was dependent on C3 but not on C5 or C6. The primary influence of tissue-bound complement was on CD4(+) T cells. Moreover, the effect of complement on alloreactive T cells was B7 dependent, shown by inhibition studies with CTLA4-Ig. These results suggest that donor epithelium-bound C3 can upregulate the alloimmune response. It is postulated that surface-bound C3 interacts with complement receptors on alloreactive T cells or on antigen presenting cells to increase allo-immune stimulation.
authors.affiliation: Department of Nephrology and Transplantation, 5th Floor, Thomas Guy House, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.forename: Hetal
authors.initials: H
authors.lastname: Patel
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Farrar
authors.forename: Roseanna E G
authors.initials: RE
authors.lastname: Hargreaves
authors.forename: Steven H
authors.initials: SH
authors.lastname: Sacks
authors.forename: Wuding
authors.initials: W
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003176:Complement C3 / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology*; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000276:immunology*; D019459:Urothelium / Q000166:cytology / Q000276:immunology
chemical_list: D003176:Complement C3