In addition to a

TCR binding affinity too low to result in apoptosis, inefficient presentation of antigens and presentation of antigen isoforms not necessarily represented in the periphery can also lead to lack of elimination of self-reactive T cells. One example that illustrates this is the presentation of a proinsulin allele in the thymus, while click here two alleles are expressed in the periphery, which is sufficient to develop a susceptibility to insulin-dependent diabetes [3]. Over recent years, the precise mechanisms by which T cells recognize peptides bound to MHC determinants have been better delineated. One of the most important conclusions from such studies is the demonstration that peptides from autoantigens are in fact presented by both MHC class II as well as MHC class I molecules. This means that, in the periphery, autoreactive T cells that have escaped thymic sorting can be kept at bay by MHC class II presentation of autoantigens. Several mechanisms maintain T cell tolerance to self in the periphery. For the sake of clarity, intrinsic and extrinsic mechanisms can be delineated Selleckchem FDA approved Drug Library [4]. In fact, mechanisms operating at T and B cell levels share many features, mediated through their antigen-specific receptor, TCR or BCR respectively. Basic principles rely on simple rules: absent or too weak receptor recognition results in ignorance. Recognition in the absence of sufficient co-stimulation drives T cells

into anergy. Specific lymphocyte deletion is the result of hyperstimulation. The capacity of T cells to edit or revise their antigen receptor in the periphery also offers yet another mechanism by which unresponsiveness can be established.

Extrinsic mechanisms deal with intervention of regulatory T cells, either from the natural repertoire selected in the thymus [5], or from adaptation of T cells in the periphery [6]. The number, phenotype, function and characteristics of subpopulations of T cells endowed with regulatory properties are, as yet, not entirely defined and are the matter of current research. Two main subsets of adaptive regulatory T cells have been established today: Tr1 and TH3 cells, which share the capacity to produce suppressive cytokines, such as IL-10 and TGF-beta [7]. We recently described another population of adaptive T cells that share properties of effector cells with a phenotype of regulatory T cells. Interestingly, such cells, named MCE公司 cT, for cytolytic T cells, can be elicited in vivo by immunization with short peptides encompassing a T cell epitope (V. Carlier, unpublished data). Their mode of action relies on both the induction of apoptosis of APC and suppression of activation of bystander T cells. The therapeutic potential of such cT is currently examined. B cells are sorted out for self-reactivity in the bone marrow. High avidity recognition results in apoptosis. However, as much as 50% of self reactive B cells can undergo BCR editing, which affects both the heavy and the light chains.