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Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide¹

David Pozo^*, Per Anderson and Elena Gonzalez-Rey^2,,

^* Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain; Institute of Parasitology and Biomedicine, Consejo Superior de Investigaciones Cientificas, Granada, Spain; and Department of Medical Biochemistry and Molecular Biology, University of Seville, Seville, Spain

T regulatory cells (Tregs) are instrumental in the maintenance of immunological tolerance. Although Treg-based immunotherapy proved successful in preclinical autoimmunity and transplantation, factors involved in the generation of human Ag-specific Tregs are poorly known. In this study, we show that treatment of human CD4⁺CD25^– T cells with the cytokine-like vasoactive intestinal peptide (VIP) during in vitro stimulation induces an anergic FoxP3⁺CD4⁺CD25^high T cell subset displaying potent regulatory activities against allospecific effector T cells, irrespective of the presence of naturally occurring Tregs. VIP-tolerant T cells are characterized by incapability to progress to S phase of cell cycle during stimulation with HLA-disparate APCs by negatively affecting the synthesis of cyclins D3 and E, the activation of cyclin-dependent kinases (cdk)2 and cdk4, and the down-regulation of the cdk inhibitor p27^kip1. VIP interaction with the type 1 VIP receptor and subsequent activation of cAMP/protein kinase A pathway play a major role in all these effects. Moreover, VIP-tolerant T cells protect against acute graft-vs-host disease in a mouse model of allogeneic bone marrow transplantation. The infusion of VIP-tolerant T cells together with the graft significantly reduces the clinical signs and mortality rate typical of the graft-vs-host disease. These effects are mediated by impairing allogeneic haplotype-specific responses of donor CD4⁺ cells in the transplanted animals. Our results suggest that including alloantigen-specific VIP-generated Tregs may be a valuable tool in therapeutic interventions to promote immunotolerance toward allogeneic grafts and to reduce the need of general immunosuppressive drugs.

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 Spanish Ministry of Education and Science (to E.G.-R.), Spanish Ministry of Health (to D.P.), Junta de Andalucia, and Spanish Collaborative Network on Multiple Sclerosis (ISCIII-RETICS-REEM).

² Address correspondence and reprint requests to Dr. Elena Gonzalez-Rey, Instituto de Parasitologia y Biomedicina, Consejo Superior de Investigaciones Cientificas, PT Ciencias Salud, Granada, 18100 Spain. E-mail address: elenag{at}ipb.csic.es

³ Abbreviations used in this paper: Treg, T regulatory cell; BMT, bone marrow transplantation; cdk, cyclin-dependent kinase; GvHD, graft-vs-host disease; int, intermediate; PCCF, pigeon cytochrome c fragment; PKA, protein kinase A; Rb, retinoblastoma gene product; pRb, phosphorylated Rb; TCD-BM, T cell-depleted bone marrow cell; VIP, vasoactive intestinal peptide; VPAC₁, type 1 VIP receptor.