Origin and T Cell Receptor Diversity of Foxp3+CD4+CD25+ T Cells

Pacholczyk, Rafał; Ignatowicz, Hanna; Kraj, Piotr; Ignatowicz, Leszek

doi:10.1016/j.immuni.2006.05.016

Cited by 284 publications

(344 citation statements)

References 48 publications

Supporting

Mentioning

303

Contrasting

Unclassified

Order By: Relevance

“…Similarly, CTLA-4-deficient mice have been shown to exhibit a skewed repertoire of Th1, Th2, and Th17 cells, which was also reported here for Tg4 CTLA-4KO mice (28,(35)(36)(37)). In our model, CDR3α using the endogenous TRAV13 showed a greater diversity in length in Treg cells than Tconv cells, which was previously found by one group (43), although other groups have found a comparable (44) or lower (45) diversity in different models.…”

Section: Discussionsupporting

confidence: 67%

“…6A). This augmented diversity has been reported before in one model but contradicted in other mouse models (43)(44)(45). The difference in CDR3 length between Tconv and Treg cells in our model was more pronounced in CTLA-4WT than CTLA4KO mice and consistent with the greater variability in TRAJ gene segment use.…”

Section: Ctla-4 Affects the Diversity And Sequence Of Endogenous Cdr3αsupporting

confidence: 76%

See 1 more Smart Citation

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

Verhagen

Genolet

Britton

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease. Tolerance to self-antigens is achieved through thymic deletion of highly autoreactive conventional T (Tconv) cells and generation of FoxP3 + regulatory T (Treg) cells. The main costimulatory molecule, CD28, augments the negative selection of Tconv cells and promotes the generation of FoxP3 + Treg cells. The role of its antagonistic homolog CTLA-4, however, remains a topic of debate. To address this topic, we investigated the thymic development of T cells in the presence and absence of CTLA-4 in a T-cell receptor (TCR) transgenic mouse model specific for the myelin basic protein peptide Ac1-9. We reveal that CTLA-4 is expressed in the corticomedullary region of the thymus. Its absence alters the response of CD4 + CD8 − thymocytes to self-antigen recognition, which affects the quantity of the Treg cells generated and broadens the repertoire of peripheral Tconv cells. T-cell repertoire alteration after deletion of CTLA-4 results from changes in TCR Vα and Jα segment selection as well as CDR3α composition in Tconv and Treg cells. CTLA-4, therefore, regulates the early development of self-reactive T cells in the thymus and plays a key role in central tolerance.costimulation | immune regulation | experimental autoimmune encephalomyelitis

show abstract

Section: Discussionsupporting

confidence: 67%

Section: Ctla-4 Affects the Diversity And Sequence Of Endogenous Cdr3αsupporting

confidence: 76%

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

Verhagen

Genolet

Britton

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The TCR repertoire expressed by Treg cells is quite broad and largely, albeit not completely, distinct from that of Tconv cells (7)(8)(9). Treg differentiation requires TCR interactions with MHC-II molecules (ref.…”

Section: Imbalanced Signal Transduction In Regulatory T Cells Expressmentioning

confidence: 99%

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

Yan

Farache

Mingueneau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

FoxP3+ T regulatory (Treg) cells have a fundamental role in immunological tolerance, with transcriptional and functional phenotypes that demarcate them from conventional CD4+ T cells (Tconv). Differences between these two lineages in the signaling downstream of T-cell receptor-triggered activation have been reported, and there are different requirements for some signaling factors. Seeking a comprehensive view, we found that Treg cells have a broadly dampened activation of several pathways and signaling nodes upon TCR-mediated activation, with low phosphorylation of CD3ζ, SLP76, Erk1/2, AKT, or S6 and lower calcium flux. In contrast, STAT phosphorylation triggered by interferons, IL2 or IL6, showed variations between Treg and Tconv in magnitude or choice of preferential STAT activation but no general Treg signaling defect. Much, but not all, of the Treg/Tconv difference in TCR-triggered responses could be attributed to lower responsiveness of antigen-experienced cells with CD44hi or CD62Llo phenotypes, which form a greater proportion of the Treg pool. Candidate regulators were tested, but the Treg/Tconv differential could not be explained by overexpression in Treg cells of the signaling modulator CD5, the coinhibitors PD-1 and CTLA4, or the regulatory phosphatase DUSP4. However, transcriptome profiling in Dusp4-deficient mice showed that DUSP4 enhances the expression of a segment of the canonical Treg transcriptional signature, which partially overlaps with the TCR-dependent Treg gene set. Thus, Treg cells, likely because of their intrinsically higher reactivity to self, tune down TCR signals but seem comparatively more attuned to cytokines or other intercellular signals.

show abstract

“…Consistent with this concept, the TCR repertoire of thymic-derived effector T (Teff) cells and Tregs has been shown to overlap to some degree [3]. Other TCR repertoire studies have not shown overlapping repertoires [4][5][6]. Further studies, focusing on the exact specificities of conventional Teff cells versus nTregs, are clearly needed, so as to better understand the implications of overlapping TCR repertoires.…”

Section: Tcr Specificity In T Cell Developmentmentioning

confidence: 99%

T cell epitope redundancy: cross-conservation of the TCR face between pathogens and self and its implications for vaccines and autoimmunity

Moise

Beseme

Tassone

et al. 2016

Expert Review of Vaccines

View full text Add to dashboard Cite

SummaryT cells are extensively trained on 'self' in the thymus and then move to the periphery, where they seek out and destroy infections and regulate immune response to self-antigens. T cell receptors (TCR) on T cells' surface recognize T cell epitopes, short linear strings of amino acids presented by antigen-presenting cells. Some of these epitopes activate T effectors, while others activate regulatory T cells. It was recently discovered that T cell epitopes that are highly conserved on their TCR face with human genome sequences are often associated with T cells that regulate immune response. These TCR-cross-conserved or 'redundant epitopes' are more common in proteins found in pathogens that have co-evolved with humans than in other noncommensal pathogens. Epitope redundancy might be the link between pathogens and autoimmune disease. This article reviews recently published data and addresses epitope redundancy, the "elephant in the room" for vaccine developers and T cell immunologists.

show abstract

Origin and T Cell Receptor Diversity of Foxp3+CD4+CD25+ T Cells

Cited by 284 publications

References 48 publications

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

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

T cell epitope redundancy: cross-conservation of the TCR face between pathogens and self and its implications for vaccines and autoimmunity

Contact Info

Product

Resources

About