Deletion of self-reactive T cells before entry into the thymus medulla

Abstract

The thymus is important in the differentiation of bone marrow-derived precursor cells into functional T cells; humoral factors, as well as physical interactions with nurse cells, dendritic cells and epithelial cells, are thought to be instrumental in this process. Thymic lymphocytes mature during their migration from the cortical to the medullary region of the thymus, when they undergo phenotypic changes that include the acquisitions of T-cell antigen receptors, hormone receptors and differentiation antigens. Cortical T cells are thus mostly CD4+CD8+, whereas medullary T cells are either CD4+CD8- or CD4-CD8+. During this period T cells are subjected to two types of repertoire selection: all T cells recognizing self-MHC with low affinity may be preferentially amplified (positive selection), and in a second step T cells with high-affinity receptors for self-MHC determinants plus self antigens are eliminated (negative selection). We have described two monoclonal antibodies specific for the V beta 6 gene segment of the alpha/beta heterodimeric T-cell antigen receptor and have shown that most CD4+/V beta 6+ T cell recognize the Mlsa antigenic determinant but not Mlsb; similar results have been reported for V beta 8.1 and Mlsa. In both situations, tolerance to Mlsa correlated in an MHC-dependent fashion with absence of V beta 6 or V beta 8.1 T-cell antigen receptor expressing T cells in the periphery. We show here by immunostaining of thymus cryosections and cytofluorometric analysis that V beta 6-expressing cortical T cells are present at high density in both Mlsa and Mlsb mice, but do not enter the medullary region of Mlsa animals.

Generation and Regulation of CD8+ Regulatory T Cells

“…Although T cell clones express receptors for foreign antigen, positive selection of these clones by self-antigens during development in the thymus means that each clone has a measurable affinity for self-antigens. Although negative selection deletes strongly self-reactive T cells (1), this process is incomplete. T cells carrying receptors with intermediate and low affinity for self-antigen are routinely released into peripheral lymphoid tissues, where they may become activated, expand and possibly initiate autoimmune disease (2).…”

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

“…Moreover, cytokines like thymic stromal lymphopoietin (TSLP) produced by epithelial cells of thymic Hassall's corpuscles promote the conversion of CD4 + CD25-thymocytes into CD4 + CD25 + Foxp3 + T regulatory cells (Tregs) [49]. Dendritic cells in the thymus are also involved in the process of central tolerance [50].…”

HLA-E–restricted regulatory CD8+ T cells are involved in development and control of human autoimmune type 1 diabetes

“…In this regard, the pioneering work of Burnet and Medawar suggested that the definition of self versus nonself is arbitrary because foreign antigens presented during fetal life are thereafter considered self (1). Moreover, it is known that all T cells are self-referential in the sense that they are positively selected for survival on self-peptide(s) bound to MHC molecules during thymic positive selection (2) before thymic negative selection, in which thymocytes expressing TCR of high avidity to self-antigens are deleted (3)(4)(5).…”

“…It is generally accepted that thymic negative selection, in which, high-avidity self-reactive thymocytes are deleted, eliminates the imminent danger of pathogenic autoimmunity in the periphery and is the major mechanism of central self-tolerance (3)(4)(5). However, while releasing the "innocent" selfreactive T cells with low avidity, thymic negative selection also allows a large fraction of self-reactive T cells of intermediate avidity to be released into the periphery under normal circumstances (10)(11)(12), and functional activation of this population of cells has the potential to elicit pathogenic autoimmunity (12)(13)(14)(15).…”