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Tolerization of dendritic cells by TS cells: the crucial role of inhibitory receptors ILT3 and ILT4

Abstract

Immunoglobulin-like transcript 3 (ILT3) and ILT4 belong to a family of inhibitory receptors expressed by human monocytes and dendritic cells. We show here that CD8+CD28 alloantigen-specific T suppressor (TS) cells induce the up-regulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering these antigen-presenting cells (APCs) tolerogenic. Tolerogenic APCs show reduced expression of costimulatory molecules and induce antigen-specific unresponsiveness in CD4+ T helper cells. Studies of human heart transplant recipients showed that rejection-free patients have circulating TS cells, which induce the up-regulation of ILT3 and ILT4 in donor APCs. These findings demonstrate an important mechanism of immune regulation.

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Figure 1: CD8+CD28 TS cells inhibit CD4+ TH cell proliferation and render APCs (monocytes, DC or KG1) tolerogenic.
Figure 2: CD8+CD28 TS cells up-regulate the expression of ILT3 and ILT4 on APCs.
Figure 3: ILT3 and ILT4 transduction of KG1 APCs.
Figure 4: Molecular and functional changes accompany ILT3 expression in KG1 APCs.
Figure 5: Expression of ILT3 and ILT4 in APCs from the spleen of transplant donors after preincubation with the recipient's CD8+CD28 T cells.
Figure 6: Cytotoxic activity of CD8+ T cells from a recipient with acute rejection.

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Acknowledgements

We thank Z. Liu, J. Fan, G. Vlad, M. Mirza and E. Ho for their help. Supported by grants from the NIH and the Interuniversitary Organ Transplantation Consortium, Rome, Italy.

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Correspondence to N. Suciu-Foca.

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Chang, C., Ciubotariu, R., Manavalan, J. et al. Tolerization of dendritic cells by TS cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol 3, 237–243 (2002). https://doi.org/10.1038/ni760

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