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

Abstract

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+CD25high 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 p27kip1. 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.

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

“…This study suggested that alloantigen-specific vasoactive intestinal peptide-generated Tregs could be a valuable tool in therapeutic interventions to promote immunotolerance toward allogeneic grafts [104]. Analogous approaches could be developed for specific autoimmune diseases.…”

“…Interestingly, cytokine-like vasoactive intestinal peptide treatment to human CD4 + CD25 -T cells resulted in the induction of an anergic CD4 + CD25 + FoxP3 + T cell subset displaying potent regulatory activities against allospecific effector T cells [104].…”

Vasoactive intestinal peptide signaling axis in human leukemia

“…One possible explanation for a low VPAC1:VPAC2 ratio in human T cell leukemia blasts compared to healthy peripheral T cells, might be due to normally low VPAC1: VPAC2 expression during T cell development as human thymocytes were found to express much higher levels of VPAC2 compared to VPAC1 [58] . This altered expression profile in leukemia blasts for the VIP receptor signaling axis could contribute to a growth advantage as VPAC1 is a potent G1/S transition arrestor by blocking the upregulation of several cyclins, while VPAC2 acts as a survival factor of mouse Th2 cells [36,52] . High levels of VIP ligand are also detected in human thymus.…”

“…In early activated T cells (5 h), the cAMP dependent CREM/ICER transcription factor is upregulated, which has been shown to "short-circuit" helix-loop-helix transcription factors that are critical for pro-inflammatory cytokine expression [48] . These microarray observations, we propose, can explain at a molecular level how the VIP signaling axis can act in an anti-inflammatory manner, as well as, induce the differentiation of activated T cells toward different effector phenotypes, including T regulatory cells and Th17 cells [36,49] . Since developing and mature T lymphocytes are heterogeneous cell populations, it will be important to generate the next generation of anti-VIP receptor antibodies capable of detecting protein within these hematopoietic subpopulations to confirm which receptor is evoking VIP-initiated signal transduction and altering metabolic cellular changes.…”

“…Recently, VIP and PACAP were discovered to increase the generation of inducible CD4 + /CD25 + regulatory T cells (iTregs) that are positive for FoxP3 expression [36] .…”