MHC class II‐independent CD25⁺ CD4⁺ CD8α β⁺ α β T cells attenuate CD4⁺ T cell‐induced transfer colitis

Abstract

CD4 + § g T cell populations that develop in mice deficient in MHC class II (through 'knockout' of either the A § , or the A g chain of the I-A b molecule) comprise a major 'single-positive' (SP) CD4 + CD8 -subset (60-90%) and a minor 'double-positive' (DP) CD4 + CD8 § g + subset (10-40%). Many DP T cells found in spleen, mesenteric lymph nodes (MLN) and colonic lamina propria (cLP) express CD25, CD103 and Foxp3. Adoptive transfer of SP but not DP T cells from A § -/-or A g -/-B6 mice into congenic RAG -/-hosts induces colitis. Transfer of SP T cells repopulates the host with only SP T cells; transfer of DP T cells repopulates the host with DP and SP T cells. Anti-CD25 antibody treatment of mice transplanted with DP T cells induces severe, lethal colitis; anti-CD25 antibody treatment of mice transplanted with SP T cells further aggravates the course of severe colitis. Hence, regulatory CD25 + T cells within (or developing from) the DP T cell population of MHC class II-deficient mice control the colitogenic potential of CD25 -CD4 + T cells.

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

“…Treg differentiation requires TCR interactions with MHC-II molecules (ref. 10 and references therein), as engagement of the TCR by agonist ligands during thymic differentiation strongly favors clonal deviation into the FoxP3+ lineage, either by inducing differentiation along the lineage (11) or because FoxP3+ cells are inherently more resistant to clonal deletion (12). Accordingly, the analysis of mice expressing a Nurr77-GFP reporter, whose expression correlates with the strength of cell activation via the TCR, showed that the reporter was generally expressed at a higher level in Treg than in Tconv cells (13).…”

Distinct Subsets of FoxP3+ Regulatory T Cells Participate in the Control of Immune Responses

“…Furthermore, the periphery of MHC II Ϫ/Ϫ mice contains CD8 ϩ CD25 ϩ T cells that exhibit contact-dependent suppressive activity analogous to that mediated by wild-type CD4 ϩ CD25 ϩ T cells (20). Other reports have indicated that a unique subset of CD4 ϩ CD8 ϩ CD25 ϩ T cells in MHC II Ϫ/Ϫ mice is enriched in FoxP3 mRNA and capable of suppressing T cellmediated inflammatory bowel disease (21). Curiously, while prevalent in MHC II Ϫ/Ϫ mice, CD8 ϩ CD25 ϩ T cells are quite rare in wild-type animals (20).…”

Foxp3-Expressing CD103+ Regulatory T Cells Accumulate in Dendritic Cell Aggregates of the Colonic Mucosa in Murine Transfer Colitis

“…18 eGFP-tg B6 mice express eGFP under the chicken ␤-actin promoter control. 17 eGFP is heterogeneously expressed from the transgene in the CD4 ϩ T-cell population of transgenic mice but remains stable within the adoptive host.…”

“…Twelve l of RNA isolated from microdissected tissue or 1 l of RNA prepared from cell suspensions, respectively, were annealed to 1 pmol of hexamer (random) primer, denatured at 80°C and reverse-transcribed as described. 18 Real-Time PCR mRNA expression was determined by real-time reverse transcriptase (RT)-PCR and relative quantification using the reference gene HPRT or CD3, respectively. Primers for HPRT and Foxp3 were as published elsewhere.…”

“…18 The tissue was digested with 0.5 mg/ml of collagenase type VIII and 5 U/ml DNase at 37°C for 90 minutes in RPMI 1640/5% v/v fetal calf serum. Lamina propria lymphoid cells were collected at the 40%/70% interface of a Percoll gradient for analysis by flow cytometry or fluorescence-activated cell sorting.…”