Establishment of tissue‐specific tolerance is driven by regulatory T cells selected by thymic epithelium

Abstract

Grafts of thymic epithelium (TE) rudiments restore T cell development and function in allogeneic athymic mice. These TE chimeras are specifically tolerant to grafts of peripheral tissues (e.g. skin and heart) from the TE donor strain, although they harbor peripheral immunocompetent T cells capable of rejecting those grafts. Initial analysis has shown that TE chimeras also harbor TE-selected CD4 T lymphocytes that inhibit graft rejection by tissue-reactive T cells in immunocompetent recipients. Peripheral tolerance in TE chimeras is thus maintained by dominant mechanisms dependent on regulatory CD4 T lymphocytes. Here we show that TE-selected regulatory T cells recruit nontolerant tissue-reactive CD4 and CD8 T cells to express similar regulatory functions. Only recent thymic emigrants, but not peripheral resident mature T cells are susceptible to this process of functional education, which also requires exposure to specific antigens and occurs entirely in the periphery. We propose that these mechanisms play a major role in establishing and maintaining natural self tolerance to tissue-specific antigens.

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

“…The findings argued that a transplanted quail thymus has the capacity to induce development of a special type of T cells with the ability to keep "xeno-reactive" T cells of recipient origin in a quite state 31,32 . The authors went on to show that such cohort of T cells which is able to act "in trans" and suppress the activity of graft-specific cells indeed exists in the periphery of chimeric animals by performing T cell transfer experiments 33,34 . In the years that followed the initial discovery of T cells with a regulatory function (hereafter referred to as Treg), Sakaguchi and colleagues have been able to show that cells mediating dominant tolerance are essential for prevention of autoimmunity, that the thymus is indispensable for the development of Treg and finally identified CD4SP cells which constitutively express the IL-2 receptor α chain (CD25) as a cell type capable of mediating suppression [35][36][37] .…”

CD8 blockade promotes the expansion of antigen-specific CD4+ FOXP3+ regulatory T cells in vivo

“…The primary role of regulatory T cells is to inhibit undesirable self-reactive immune responses [1,2]. Regulatory T cells can be divided into subsets on the basis of their development (natural or acquired), cell surface phenotype, secreted proteins and function.…”

Kinetics and Repertoire Selection of T Cells Derived from the Early Waves of Fetal Thymus Colonization After Thymus Grafting in Allogeneic Nude Recipients

“…In physiological conditions, the survival of early autoreactive thymocytes might play a role in the establishment and maintenance of the T cell repertoire and of self tolerance. We have recently shown that regulatory cells can be selected on thymic epithelium [29], and that such cells are able to recruit, by education of recent thymic emigrants, a second wave of tissue specific regulatory T cells [30]. Thus, the survival of the first wave of T cells exported to the periphery may be fundamental to trigger the process of regulation that leads to the establishment of self tolerance.…”