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TITLE: DENDRITIC CELLS MEDIATE A T-SUPPRESSOR CELL CASCADE VIA THE INHIBITORY RECEPTORS ILT3 AND ILT4

John S Manavalan ¹, Paola C Rossi ¹, George Vlad ¹, Anna Yarilina ¹, Raffaello Cortesini ¹ and Nicole Suciu-Foca ¹.

¹Division of Immunogenetics, Dept. of Pathology, Columbia University Colege of Physicians and Surgeons, New York, New York.

While immunosuppressive drugs have an important role in preventing transplant rejection and attenuating the course of autoimmune diseases, they act nonspecifically on the immune system leaving the patients vulnerable to infections and increased incidence of malignancies. The modulation of the immune response to specific antigens has remained the ultimate goal in treatment of patients with transplants, autoimmune diseases, chronic viral diseases and cancer. Dendritic cells (DC) have emerged as a key component of the immune system involved in the induction of peripheral tolerance. In previous work we have shown that when immature DC interact with antigen specific CD8+CD28- T suppressor cells (TS), they become tolerogenic via the upregulation of the inhibitory receptors, Immunoglobulin like transcript 3 (ILT3) and ILT4, on their surface and anergize naive CD4+ T cells. The phenotype acquired by the anergized CD4+ TH resemble that of CD4+CD45RO+CD25+ regulatory T cells (TR) described in rodents and humans. Since other studies have shown that anergic CD4+ CD45RO+ CD25+ T cells inhibit T cell alloreactivity, we explored the possibility that TH anergized by tolerogenic Antigen Presenting Cells (APC) also acquire suppressive function. Our experiments, using CD8 depleted and CD8 non depleted T cell lines (TCL), showed that only alloreactive CD4+ CD45RO+ CD25+ T cells generated in the presence of CD8+ T cells, were able to tolerize other APC by upregulating the surface expression of ILT3 and ILT4. In turn, APC tolerized by anergic CD4+ CD45RO+ CD25+ TR cells inhibited the alloreactivity of other CD4+ TH cells, thus continuing the cascade of suppression. The suppressive activity of these CD4+CD45RO+CD25+ TR cells was found to be antigen specific, cytokine-independant and contact dependant requiring the presence of APC.