ALLOANTIGEN SPECIFIC CD8+CD28- FOXP3+ T SUPPRESSOR CELLS TOLERIZE BOTH PROFESSIONAL APC, SUCH AS DC, AND NON-PROFESSIONAL APC SUCH AS EC BY UPREGULATING THE CELL SURFACE EXPRESSION OF INHIBITORY RECEPTORS.

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ALLOANTIGEN SPECIFIC CD8⁺CD28^- FOXP3⁺T SUPPRESSOR CELLS TOLERIZE BOTH PROFESSIONAL APC, SUCH AS DC, AND NON-PROFESSIONAL APC SUCH AS EC BY UPREGULATING THE CELL SURFACE EXPRESSION OF INHIBITORY RECEPTORS.
John S. Manavalan, MD, Luigi Scotto, PhD, Seunghee Kim-Shulze, PhD, Afzal J. Naiyer, MD, George Vlad, Sara Galluzzo, MD, Raffaello Cortesini, MD and Nicole Suciu-Foca, PhD. New York City NY, USA, Columbia University, College of Physicians and Surgeons, 10032, Department of Pathology.

T suppressor and Regulatory cells have been shown to play an important role in the maintenance of central and peripheral tolerance thereby preventing allograft rejection, autoimmunity and allergy. We have previously described a distinct population of allo specific CD8⁺CD28^- T suppressor (T_S) generated in vitro after multiple rounds of stimulation of human peripheral blood mononuclear cells (PBMCs) with either allogeneic- or xenogeneic-donor APCs. Molecular characterization of CD8⁺CD28^- T_S cells revealed that, similar to naturally-occurring CD4⁺CD25⁺ TR cells, T_S are FoxP3⁺, CTLA-4⁺ GITR⁺ and TNFR2⁺. As compared to CD8⁺CD28⁺ cytotoxic T cells from the same allospecific T cell line, CD8⁺CD28^- T_S cells displayed increased mRNA expression of inhibitory NK receptors such as KIR3DL1, KIR3DL2 and KIR2DL3. CD8⁺ T_S are MHC class I–restricted and tolerize both professional APC, such as DC, and non-professional APC such as EC by upregulating the cell surface expression of inhibitory receptors Immunoglobulin like transcript (ILT)-3 and ILT4 and downregulating the expression of costimulatory molecules. Tolerized ILT3^high, ILT4^high DC or ILT4⁺ HLA-DR⁺ EC anergize CD4⁺ T_H cells. In addition, tolerogenic ILT4⁺ EC can elicit the differentiation of CD8⁺CD28^- FoxP3⁺ T cells. Alloantigen specific CD8⁺CD28^-FOXP3⁺ T cells, which trigger the upregulation of inhibitory receptors in endothelial cells, are present in the circulation of heart allograft recipients in quiescence.