Peptide Specificity of Thymic Selection of CD4+CD25+ T Cells

Abstract

The CD4+CD25+ regulatory T cells can be found in the thymus, but their need to undergo positive and negative selection has been questioned. Instead, it has been hypothesized that CD4+CD25+ cells mature following TCR binding to MHC backbone, to low abundant MHC/peptide complexes, or to class II MHC loaded with peripheral autoantigens. In all these circumstances, processes that are distinct from positive and negative selection would govern the provenance of CD4+CD25+ cells in the thymus. By comparing the development of CD4+CD25− and CD4+CD25+ cells in mice expressing class II MHC molecules bound with one or many peptide(s), we show that the CD4+CD25+ cells appear during natural selection of CD4+ T cells. The proportion of CD4+CD25+ cells in the population of CD4+ thymocytes remains constant, and their total number reflects the complexity of selecting class II MHC/peptide complexes. Hence, thymic development of CD4+CD25+ cells does not exclusively depend on the low-density, high-affinity MHC/peptide complexes or thymic presentation of peripheral self-Ags, but, rather, these cells are selected as a portion of the natural repertoire of CD4+ T cells. Furthermore, while resistant to deletion mediated by endogenous superantigen(s), these cells were negatively selected on class II MHC/peptide complexes. We postulate that while the CD4+CD25+ thymocytes are first detectable in the thymic medulla, their functional commitment occurs in the thymic cortex.

Antigen Specificity Is not Required for Modulation of Lung Allergic Responses by Naturally Occurring Regulatory T Cells

“…These results, however, did not exclude the role of ␣␤TCRs or address the issue of Ag-specificity in suppression as reported in previous studies (22)(23)(24)(25)(26). There are studies providing evidence supporting intrathymic development and selection as well as the peripheral expansion of nTregs involving self MHC II/peptide diversities (27,28). Expression of endogenous TCR␣-chains may be necessary in some situations for the development of nTregs (29 -31) but not in TCR transgenic RAG Ϫ/Ϫ mice expressing the OVA peptide (32) or RAG Ϫ/Ϫ mice expressing influenza hemagglutinin under the control of the Ig k promoter (33).…”

“…This interaction between TCRs and self-Ags is proposed as important for the development and selection of nTregs in the thymus (27,28). Unlike conventional CD4 ϩ CD25 Ϫ T cells, which recognize foreign Ags in the context of MHC II and ␣␤ ϩ TCRs, the evidence for a requirement or involvement of Ag-specific TCRs on nTregs in the induction and expression of regulatory function in vivo is limited and somewhat conflicting.…”

Development of CD25– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

“…However, we also show that they share a key property with Tr1 cells [35]: the capacity to produce both high levels of IL-10 and Foxp3 transcripts, but not of IL-2. Their other characteristics are close to some of the well-established properties of natural CD25 + regulatory T cells, such as the need for cellular contact [36], the absence of in vitro IL-4-mediated effects [36][37][38][39], the reversal of the inhibition by exogenous IL-2 [40] and the absence of CDR3 length distribution biases (our unpublished data) [41][42][43]. The origin of the regulatory CD25 -T cells are not yet known, and further experiments are needed to better understand their similarities and differences with CD4 + regulatory T cells induced by immature DC in vitro.…”

Shaping of the Autoreactive Regulatory T Cell Repertoire by Thymic Cortical Positive Selection

“…However, in mice expressing a single MHC/peptide ligand by all normally MHC class II-expressing stromal cells, a diverse Treg repertoire develops. In these mice, also negatively selecting dendritic cells express the single ligand, and Treg from such mice do not respond to the selecting ligand (30,59,60). Therefore, even if agonist self-ligands expressed by TEC clearly favor development of Treg, they probably are not the only ones to do so.…”