Induction of alloantigen-specific human T regulatory cells by vasoactive intestinal peptide.
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.
Pozo
David
D
Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Anderson
Per
P
Gonzalez-Rey
Elena
E
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000628:therapy; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000637:transplantation; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage / Q000502:physiology* / Q000627:therapeutic use
D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D007519:Isoantigens; D014660:Vasoactive Intestinal Peptide