Inhibitory Feedback Loop Between Tolerogenic Dendritic Cells and Regulatory T Cells in Transplant Tolerance

• Published in: The Journal of immunology (1950) Vol. 170; no. 3; pp. 1304 - 1312
• Main Authors: Min, Wei-Ping, Zhou, Dejun, Ichim, Thomas E, Strejan, Gill H, Xia, Xiaoping, Yang, Jinming, Huang, Xuyan, Garcia, Bertha, White, David, Dutartre, Patrick, Jevnikar, Anthony M, Zhong, Robert
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.02.2003
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; CD4-Positive T-Lymphocytes - immunology; Cell Communication - drug effects; Cell Communication - immunology; Cells, Cultured; Dendritic Cells - drug effects; Dendritic Cells - immunology; Drug Synergism; Feedback - drug effects; Guanidines - pharmacology; Heart Transplantation - immunology; Immunosuppressive Agents - pharmacology; Leukocyte Common Antigens - immunology; Lymphocyte Activation - immunology; Lymphocyte Culture Test, Mixed; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; T-Lymphocyte Subsets - immunology; Transplantation Tolerance - drug effects; Transplantation Tolerance - immunology; Transplantation, Heterotopic
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.3.1304

An active role of T regulatory cells (Treg) and tolerogenic dendritic cells (Tol-DC) is believed important for the induction and maintenance of transplantation tolerance. However, interactions between these cells remain unclear. We induced donor-specific tolerance in a fully MHC-mismatched murine model of cardiac transplantation by simultaneously targeting T cell and DC function using anti-CD45RB mAb and LF 15-0195, a novel analog of the antirejection drug 15-deoxyspergualin, respectively. Increases in splenic Treg and Tol-DC were observed in tolerant recipients as assessed by an increase in CD4(+)CD25(+) T cells and DC with immature phenotype. Both these cell types exerted suppressive effects in MLR. Tol-DC purified from tolerant recipients incubated with naive T cells induced the generation/expansion of CD4(+)CD25(+) Treg. Furthermore, incubation of Treg isolated from tolerant recipients with DC progenitors resulted in the generation of DC with Tol-DC phenotype. Treg and Tol-DC generated in vitro were functional based on their suppressive activity in vitro. These results are consistent with the notion that tolerance induction is associated with a self-maintaining regulatory loop in which Tol-DC induce the generation of Treg from naive T cells and Treg programs the generation of Tol-DC from DC progenitors.