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*Department of Molecular Biomedicine and
Department of Cellular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
Dendritic cells (DCs) are professional APCs involved in the initiation of both immunity and immunological tolerance. In autoimmune diseases or graft rejections, most reactive lymphocytes are effector/memory cells. It is believed that memory T cells are more resistant to tolerance induction than naive lymphocytes; however, studies on mechanisms for their efficient tolerization are still scarce. In this study, we generated human monocyte-derived DCs by culture with GM-CSF and IL-4 (control DCs), as well as tolerogenic DCs (tDCs) by adding IL-10, IL-10/TGF-β1, or IL-10/IL-6. Cells were maturated with TNF-
/PGE2. Compared with control DCs, tDCs had similar expression of HLA-DR, CD80, and CD86, lower expression of CD40, higher levels of macrophage markers, enhanced endocytic ability, increased secretion of IL-6, IL-10 (only tDCs generated with IL-10 and tDCs generated with IL-10/IL-6), and PGE2, and lower secretion of IL-12 and IL-23. In vitro, tDCs had the capacity to induce anergy in tetanus toxoid-specific memory CD4+ T cells, whereas the proliferative response to an unrelated Ag was intact. Anergy could be reverted upon exposure to IL-2. tDC-primed T cells have low suppressive ability. Nevertheless, the generation of both anergic and regulatory T cells was more efficient with tDCs generated with IL-10/TGF-β1. Microarray-based gene expression profiling reflected modulated expression of several transcripts in tDCs. Surface CLIP–HLA-DR complexes and intracellular thrombospondin-1 were increased in the three tDCs. CD39 was highly expressed only in tDC-TGF, which correlated with increased adenosine production. We propose that these molecules, together with IL-10 and prostanoids, are key factors to induce Ag-specific tolerance in memory T cells.
Address correspondence and reprint requests to Dr. Carmen Sanchez-Torres, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV-IPN), Department of Molecular Biomedicine, Av. I.P.N. 2508, C.P. 07360, Mexico City, Mexico. E-mail address: csanchez{at}cinvestav.mx
1 Current address: Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
This work was supported by a grant to C.S.-T. from Secretaría de Educación Pública-Consejo Nacional de Ciencia y Tecnología (42712-Q). H.T.-A., S.R.A.-R., and G.G.-P. are recipients of Consejo Nacional de Ciencia y Tecnología predoctoral scholarships (180583, 180592, and 180578, respectively).
The sequences presented in this article have been submitted to the National Center for Biotechnology Information’s Gene Expression Omnibus under accession number GSE18921.
The online version of this paper contains supplemental material.
Abbreviations used in this paper:
cDC, control dendritic cell; cT, control T lymphocyte; DC, dendritic cell; DMPX, 3,7-dimethyl-1-propargylxanthine; DX, dextran; Foxp3, forkhead box p3; FTH1, ferritin heavy polypeptide 1; iDC, immature dendritic cell; ILT, Ig-like transcript; iTSP-1, intracellular thrombospondin 1; L-NAME, L-nitro-arginine methyl ester; M
, macrophage; mDC, mature dendritic cell; MFI, mean fluorescence intensity; rT, T cell with no prior stimulation in vitro; tDC, tolerogenic dendritic cell; tDC-IL6, tolerogenic dendritic cell generated with IL-10/IL-6; tDC-IL10, tolerogenic dendritic cell generated with IL-10; tDC-TGF, tolerogenic dendritic cell generated with IL-10/TGF-β1; Tind, indicator responder T cell; Treg, regulatory T cell; TSP-1, thrombospondin 1; tT, tolerant T lymphocyte; TT, tetanus toxoid; tT-IL10, tolerant IL10 T cell; tT-TGF, tolerant TGF T cell; tT-IL6, tolerant IL6 T cell.
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