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Ig-Like Transcript 3 Regulates Expression of Proinflammatory Cytokines and Migration of Activated T Cells¹

Chih-Chao Chang^*, Zhuoru Liu^*, George Vlad^*, Haiyan Qin^*, Xugang Qiao^*, Donna M. Mancini, Charles C. Marboe^*, Raffaello Cortesini^* and Nicole Suciu-Foca^2,*

^* Department of Pathology and Department of Medicine, Columbia University, New York, NY 10032

Ig-like transcript 3 (ILT3), an inhibitory receptor expressed by APC is involved in functional shaping of T cell responses toward a tolerant state. We have previously demonstrated that membrane (m) and soluble (s) ILT3 induce allogeneic tolerance to human islet cells in humanized NOD/SCID mice. Recombinant sILT3 induces the differentiation of CD8⁺ T suppressor cells both in vivo and in vitro. To better understand the molecular mechanisms by which ILT3 suppresses immune responses, we have generated ILT3 knockdown (ILT3KD) dendritic cells (DC) and analyzed the phenotypic and functional characteristics of these cells. In this study, we report that silencing of ILT3 expression in DC (ILT3KD DC) increases TLR responsiveness to their specific ligands as reflected in increased synthesis and secretion of proinflammatory cytokines such as IL-1, IL-1β, and IL-6 and type I IFN. ILT3KD-DC also secretes more CXCL10 and CXCL11 chemokines in response to TLR ligation, thus accelerating T cell migration in diffusion chamber experiments. ILT3KD-DC elicit increased T cell proliferation and synthesis of proinflammatory cytokines IFN- and IL-17A both in MLC and in culture with autologous DC pulsed with CMV protein. ILT3 signaling results in inhibition of NF-B and, to a lesser extent, MAPK p38 pathways in DC. Our results suggest that ILT3 plays a critical role in the in control of inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Juvenile Diabetes Research Foundation (1-2008-550) and the Interuniversitary Organ Transplantation Consortium (Rome, Italy).

² Address correspondence and reprint requests to Dr. Nicole Suciu-Foca, Columbia University, Department of Pathology, 630 West 168th Street, P&S 14-401, New York, NY 10032. E-mail address: ns20{at}columbia.edu

³ Abbreviations used in this paper: ILT3, Ig-like transcript 3; ctrl-DC, control DC; DC, dendritic cell; ILT3KD, ILT3 knockdown; INDO, indoleamine-pyrrole 2,3-dioxygenase; IKKβ, IB kinase β; p, phosphorylated; polyI:C, polyinosinic-polycytidylic acid; SHP, Src homology region 2 domain-containing phosphatase; sILT3, soluble ILT3; siRNA, small interfering RNA; Ts, T suppressor cell.