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GENERATION OF TOLEROGENIC ANTIGEN PRESENTING CELLS: CRUCIAL ROLE OF INHIBITORY RECEPTORS ILT3 AND ILT4.
John S. Manavalan, MD , George Vlad BS , Seunghee Kim-Shulze PhD , Paola Rossi MD , Flavia Piazza PhD , Raffaello Cortesini MD and Nicole Suciu-Foca PhD . New York NY, USA, College of Physicians and Surgeons of Columbia University, 10032, Department of Pathology .
The inhibitory receptors ILT3 and ILT4, expressed on monocytes and dendritic cells (DC), belong to a family of immunoglobulin-like inhibitory receptors (ILTs or LIRs) that display a long cytoplasmic tail containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and inhibit cell activation by recruiting the tyrosine phosphatase SHP-1. Our studies show that ILT3 and ILT4 gene expression and cell surface expression is upregulated in APC upon exposure to allospecific CD8+ CD28- T suppressor cells (TS), CD4+ CD25+ CD45RO+ T regulatory cells (TR) or regulatory cytokines, such as IL-10 and/or IFNα. These APC expressing high levels of ILT3 and ILT4, become tolerogenic and render unprimed or primed CD4+ TH cells anergic. These anergic CD4+ TH cells, in turn, acquire suppressive activity mediated by ILT3 and ILT4. To study the mechanism of ILT3 and ILT4 induction APC were transfected with the cloned ILT3 promoter (-1134 to +1) or ILT4 promoter (-1860 to +1) using a dual luciferase reporter system. Promoter activity was induced by exposure of the promoter transfected APC with TS, TR or treatment with 1α, 25 dihydroxyvitamin D3 but not by treatment with FK506 or Cyclosporin A. Taken together these data demonstrate that a common feature of tolerogenic APC is the upregulation of inhibitory receptors. The use of the ILT3 and ILT4 promoters in the luciferase reporter assay provides a reliable tool for testing cytokines and pharmaceuticals with immunomodulatory activity.