Tracking the Immunoregulatory Mechanisms Active During Allograft Tolerance

• Published in: The Journal of immunology (1950) Vol. 168; no. 5; pp. 2274 - 2281
• Main Authors: Sanchez-Fueyo, Alberto, Weber, Martina, Domenig, Christoph, Strom, Terry B, Zheng, Xin Xiao
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01-03-2002
• Subjects: AB7 antigen; Abatacept; Adoptive Transfer; Animals; Antibodies, Monoclonal - pharmacology; Antigens, CD; Antigens, Differentiation - immunology; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; CTLA-4 Antigen; CTLA-4 protein; Graft Rejection - immunology; Immunoconjugates; Interleukin-2 - pharmacology; Islets of Langerhans Transplantation - immunology; Isoantigens - immunology; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Lymphocyte Depletion; Mice; Mice, Inbred DBA; Receptors, Interleukin-2 - immunology; Spleen - immunology; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; T-Lymphocytes, Regulatory - immunology; Transplantation Tolerance - immunology; Transplantation, Homologous
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.5.2274

Immunoregulatory mechanisms dependent on regulatory CD4+ T cells are believed to be critical in the maintenance of peripheral tolerance to allografts. However, a detailed characterization of the effects of these regulatory T cells has been hampered by the absence of a simple means to track and study them. In this work we provide evidence that in a murine model of islet transplantation the interactions between alloaggressive and regulatory T cells can be studied in vitro and in vivo at the single-cell level. The observations made in both an in vitro coculture system and an in vivo CFSE-based adoptive transfer model indicate that lymphocytes from tolerant allograft recipients 1) proliferate weakly to donor strain allogeneic cells but vigorously to third-party strain cells; and 2) suppress the proliferation of naive syngeneic CD4+ and CD8+ T cells to donor tissue in a cell dose- and Ag-specific manner. These effects depend on the presence of CD4+CD25+ T cells and are neutralized by anti-CTLA4 mAb or rIL-2. The principal effect of anti-CTLA4 is directed against the naive, not regulatory, T cell population. These results can be replicated in vivo by transferring lymphocyte populations into transplant recipients, proving that the graft-protecting actions of regulatory T cells are blunted by a rise in the number of allodestructive T cells (pool size model) and depend on the presence of CD4+CD25+ T cells and the integrity of the CTLA4/B7 pathway.