The Thymic Niche Does Not Limit Development of the Naturally Diverse Population of Mouse Regulatory T Lymphocytes

Romagnoli, Paola; Dooley, James; Enault, Geneviève; Vicente, Rita; Malissen, Bernard; Liston, Adrian; Meerwijk, Joost P. M. van

doi:10.4049/jimmunol.1201564

Cited by 9 publications

(3 citation statements)

References 48 publications

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“…Even though background MUC1 expression in MUC1.Tg mice naturally skews the anti-MUC1 T-cell repertoire compared to WT mice, there were no discernible differences in generated T-cell avidity ( S1 Fig ) [ 45 ]. Thus, consistent with previous reports, we did not observe evidence for thymic deletion of high affinity responses, suggesting that MUC1 tolerance is largely a reversible peripheral phenomenon [ 51 ]. Furthermore, immunotargeting MUC1 could be used to achieve major therapeutic effects without engendering detectable autoimmune toxicity.…”

Section: Discussionsupporting

confidence: 93%

MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice

et al. 2016

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It remains challenging to produce decisive vaccines against MUC1, a tumor-associated antigen widely expressed by pancreas, breast and other tumors. Employing clinically relevant mouse models, we ruled out such causes as irreversible T-cell tolerance, inadequate avidity, and failure of T-cells to recognize aberrantly glycosylated tumor MUC1. Instead, every tested MUC1 preparation, even non-glycosylated synthetic 9mer peptides, induced interferon gamma-producing CD4+ and CD8+ T-cells that recognized glycosylated variants including tumor-associated MUC1. Vaccination with synthetic peptides conferred protection as long as vaccination was repeated post tumor challenge. Failure to revaccinate post challenge was associated with down-regulated tumor MUC1 and MHC molecules. Surprisingly, direct admixture of MUC1-expressing tumor with MUC1-hyperimmune T-cells could not prevent tumor outgrowth or MUC1 immunoediting, whereas ex vivo activation of the hyperimmune T-cells prior to tumor admixture rendered them curative. Therefore, surrogate T-cell preactivation outside the tumor bed, either in culture or by repetitive vaccination, can overcome tumor escape.

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Section: Discussionsupporting

confidence: 93%

MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice

et al. 2016

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“…These experiments reinforced the role of TCR specificity in Treg thymic selection and suggested a model in which intraclonal competition limits the number of T cells of a given specificity that can develop into Tregs 18 , 19 . Whether such niche constraints restrict Treg differentiation in the context of a diverse repertoire of precursors remains less clear 20 .…”

Section: Tcr-transgenic Tregs: a Window On Treg Thymic Selectionmentioning

confidence: 99%

Homeostasis and function of regulatory T cells (Tregs) in vivo: lessons from TCR‐transgenic Tregs

Attridge

Walker

2014

Immunological Reviews

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The identification of CD25 and subsequently Forkhead box protein 3 (Foxp3) as markers for regulatory T cells (Tregs) has revolutionized our ability to explore this population experimentally. In a similar vein, our understanding of antigen-specific Treg responses in vivo owes much to the fortuitous generation of T-cell receptor (TCR)-transgenic Tregs. This has permitted tracking of Tregs with a defined specificity in vivo, facilitating analysis of how encounter with cognate antigen shapes Treg homeostasis and function. Here, we review the key lessons learned from a decade of analysis of TCR-transgenic Tregs and set this in the broader context of general progress in the field. Use of TCR-transgenic Tregs has led to an appreciation that Tregs are a highly dynamic proliferative population in vivo, rather than an anergic population as they were initially portrayed. It is now clear that Treg homeostasis is positively regulated by encounter with self-antigen expressed on peripheral tissues, which is likely to be relevant to the phenomenon of peripheral repertoire reshaping that has been described for Tregs and the observation that the Treg TCR specificities vary by anatomical location. Substantial evidence has also accumulated to support the role of CD28 costimulation and interleukin-2 in Treg homeostasis. The availability of TCR-transgenic Tregs has enabled analysis of Treg populations that are sufficient or deficient in particular genes, without the comparison being confounded by repertoire alterations. This approach has yielded insights into genes required for Treg function in vivo, with particular progress being made on the role of ctla-4 in this context. As the prospect of manipulating Treg populations in the clinic becomes reality, a full appreciation of the rules governing their homeostasis will prove increasingly important.

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“…B6 mice expressing the Foxp3-Thy1 a mutation and a Rag2-Gfp transgene were previously described (26). The two mutations were introduced into the NOD genetic background by speed-backcrossing (27).…”

Section: Micementioning

confidence: 99%

The Repertoire of Newly Developing Regulatory T Cells in the Type 1 Diabetes–Prone NOD Mouse Is Very Diverse

et al. 2021

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Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen-specificity of Treg plays an important role in their in vivo activity. We therefore assessed the diversity of the T cell receptors for antigen (TCR) expressed by Treg newly developed in the thymus of autoimmune type I diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that usage of the TCR and TCR variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCR and TCR chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type I diabetes in the NOD mouse.

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The Thymic Niche Does Not Limit Development of the Naturally Diverse Population of Mouse Regulatory T Lymphocytes

Cited by 9 publications

References 48 publications

MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice

MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice

Homeostasis and function of regulatory T cells (Tregs) in vivo: lessons from TCR‐transgenic Tregs

The Repertoire of Newly Developing Regulatory T Cells in the Type 1 Diabetes–Prone NOD Mouse Is Very Diverse

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