Mechanisms of tolerance induction: blockade of co–stimulation

Abstract

Induction of tolerance to transplantation antigens is believed to be a promising way to achieve long-term allograft survival without a deleterious immunosuppressive regimen. T-cell activation, which is an essential feature of graft rejection, requires a ¢rst signal provided by T-cell receptor (TCR) ligation and a second signal provided by engagement of co-stimulatory molecules with their respective ligands on antigen-presenting cells. The coordinated triggering of these two independent signalling systems ensures the full T-cell activation, including proliferation and acquisition of e¡ector function. TCR occupancy in the absence of co-stimulatory signals leads to a sustained loss of antigen responsiveness called clonal anergy, which could be of major importance in transplantation. In vivo, co-stimulation blockade was indeed shown to allow for long-term allograft survival in several transplantation models. However, the current continuous identi¢cation of new co-stimulatory molecules suggests that a functional redundancy of the system exists and that tolerance to transplantation antigens might be achieved more easily through the combined blockade of two or several co-stimulatory signals.In this review, we analyse the biological e¡ects of the disruption of some co-stimulation pathways in vitro and in vivo and discuss their potential interest for tolerance induction.

Idiotypic T cells specific for Morbillivirus nucleocapsid protein process and present their TCR to cognate anti-idiotypic CD8+ T cells

“…We have also shown T cell-T cell interactions by cell adhesion assay, which are idiotypic TCR specific, and which depend on the processing and presentation of idiotypic TCR. It is interesting to note that only in vitro activated idiotypic T cells are able to induce Bcl-2 expression and cytokine secretion, which is in contrast to earlier reports where presentation of antigen by T cells to other T cells leads to the induction of tolerance and anergy [34,57]. This is probably due to lack of co-stimulatory molecules on idiotypic T cells.…”

Differences in the Kinetics, Amplitude, and Localization of ERK Activation in Anergy and Priming Revealed at the Level of Individual Primary T Cells by Laser Scanning Cytometry

“…Once it is induced, it can suppress many aspects of the Ag-specific immune response to subsequent challenge, including lymphocyte proliferation, cytokine production, in vivo delayed-type hypersensitivity, and Ab production (2). However, the molecular mechanisms underlying this phenomenon remain unclear (3,4).…”

Activated mouse T cells downregulate, process and present their surface TCR to cognate anti‐idiotypic CD4+ T cells

“…The IL‐2 secretion and proliferation results show that nonactivated anti‐idiotypic T cells do not secrete IL‐2. It is known that naive T cells lack costimulatory molecules, 30 and presentation of antigen in the absence of costimulatory molecules leads to the generation of tolerance and anergy in T cells 56 . Further experiments are necessary to explain the presence of TCR variable region peptide on the MHC class II molecule on the surface of T cells.…”