Generation of CD4+CD25+ Regulatory T Cells from Autoreactive T Cells Simultaneously with Their Negative Selection in the Thymus and from Nonautoreactive T Cells by Endogenous TCR Expression

Abstract

Normal T cell repertoire contains regulatory T cells that control autoimmune responses in the periphery. One recent study demonstrated that CD4+CD25+ T cells were generated from autoreactive T cells without negative selection. However, it is unclear whether, in general, positive selection and negative selection of autoreactive T cells are mutually exclusive processes in the thymus. To investigate the ontogeny of CD4+CD25+ regulatory T cells, neo-autoantigen-bearing transgenic mice expressing chicken egg OVA systemically in the nuclei (Ld-nOVA) were crossed with transgenic mice expressing an OVA-specific TCR (DO11.10). Ld-nOVA × DO11.10 mice had increased numbers of CD4+CD25+ regulatory T cells in the thymus and the periphery despite clonal deletion. In Ld-nOVA × DO11.10 mice, T cells expressing endogenous TCR αβ chains were CD4+CD25− T cells, whereas T cells expressing autoreactive TCR were selected as CD4+CD25+ T cells, which were exclusively dominant in recombination-activating gene 2-deficient Ld-nOVA × DO11.10 mice. In contrast, in DO11.10 mice, CD4+CD25+ T cells expressed endogenous TCR αβ chains, which disappeared in recombination-activating gene 2-deficient DO11.10 mice. These results indicate that part of autoreactive T cells that have a high affinity TCR enough to cause clonal deletion could be positively selected as CD4+CD25+ T cells in the thymus. Furthermore, it is suggested that endogenous TCR gene rearrangement might critically contribute to the generation of CD4+CD25+ T cells from nonautoreactive T cell repertoire, at least under the limited conditions such as TCR-transgenic models, as well as the generation of CD4+CD25− T cells from autoreactive T cell repertoire.

Deficiency of the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP-1) Causes Enrichment of CD4+CD25+ Regulatory T Cells

“…Thymi and spleens of me/me mice are enriched for CD4 ϩ CD25 ϩ T cells Because high-avidity peptide:TCR interactions can lead to an increase in the number of T reg cells (11)(12)(13), it is thought that the strength of TCR signaling also regulates T reg cell development. We therefore examined whether SHP-1, through regulation of TCR signal strength, is involved in the generation of T reg cells.…”

“…Although the necessity for the second V␣ chain is not fully understood and has even been shown to be superfluous under certain conditions (12,13), several nontransgenic V␣ chains have been reported to be enriched in the T reg cell population (40). V␣2 has been found to be expressed on 11-15% of the DO11:ϩ/ϩ T reg cells.…”

“…Moreover, thymectomy at day 3 results in autoimmune disease (5), which can be prevented by the transfer of CD4 ϩ CD25 ϩ T reg cells (8). Second, in TCR transgenic (Tg) mice, exposure of the developing T cells to the cognate peptide in the thymus caused an increase in the CD4 ϩ CD25 ϩ T reg cell population (11)(12)(13). Interestingly, exposure to low-affinity peptides failed to induce an increased T reg cell population.…”

Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

“…Studies on nTreg development suggest a model in which strong TCR signals against self-Ags specify developing thymocytes to the Treg lineage (7,43). According to this model, interaction with self-Ags in the periphery allows Tregs to proliferate and maintain their numbers in the steady-state (8,21,23,25).…”

Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL‐)two to tango

“…(1) TCR triggering alone does not induce full suppressive activity in Treg. This is of fundamental relevance since most Treg probably recognize autoantigens with high affinity [42][43][44][45] and are thus constantly activated by antigen in vivo [46], which would result in permanent systemic suppression. (2) Treg activation depends on a second neighbouring cell providing IL-2.…”