Affinity-Based Selection of Regulatory T Cells Occurs Independent of Agonist-Mediated Induction of Foxp3 Expression

Relland, Lance M.; Mishra, Manoj K.; Haribhai, Dipica; Edwards, Brandon; Ziegelbauer, Jennifer; Williams, Calvin B.

doi:10.4049/jimmunol.182.3.1341

Cited by 31 publications

(23 citation statements)

References 72 publications

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“…Alternatively the high concentrations of OVAp-loaded MHC complexes on thymic DCs may dictate the outcome. Several studies have indeed correlated TCR affinity and signal strength with differential effects on clonal deletion versus Treg induction (Atibalentja et al, 2009; Jordan et al, 2001; Relland et al, 2009; Starr et al, 2003). However, it is also possible that pDCs are intrinsically inefficient at inducing Tregs in the thymic environment as shown in a polyclonal thymocyte-DC co-culture system, in which migratory SIRPα+ cDCs, but not thymic pDCs or resident SIRPα− cDCs, induced natural Treg development (Proietto et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance

et al. 2012

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SUMMARY Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets remain poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry of endogenous or i.v. transfused pDCs. pDCs activated by Toll-like receptor (TLR) ligands downregulated CCR9 and lost their ability to home to the thymus. Moreover, endogenous pDCs took up subcutaneously injected fluorescent Ag and, in the absence of TLR signals, transported Ag to the thymus in a CCR9-dependent fashion. Injected, Ag-loaded pDCs effectively deleted Ag-specific thymocytes, and this thymic clonal deletion required CCR9-mediated homing and was prevented by infectious signals. Thus peripheral pDCs can contribute to immune tolerance through CCR9-dependent transport of peripheral Ags and subsequent deletion of Ag-reactive thymocytes.

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Section: Discussionmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance

et al. 2012

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“…It remains to be seen whether similar results would be obtained in a system involving tissuerestricted self-antigens, where lower levels of thymic selfpMHCII expression or preferential expression in distinct antigen-presenting cell types may be more conducive for Treg cell development in a greater number of clones (36). (37,38). However, it is also possible that the presence of 2W antigen may have induced the expression of Foxp3 in T cells that would not have done so otherwise in WT mice.…”

Section: Discussionmentioning

confidence: 99%

Quantitative impact of thymic selection on Foxp3 ⁺ and Foxp3 ⁻ subsets of self-peptide/MHC class II-specific CD4 ⁺ T cells

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et al. 2011

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

105

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It is currently thought that T cells with specificity for self-peptide/ MHC (pMHC) ligands are deleted during thymic development, thereby preventing autoimmunity. In the case of CD4 + T cells, what is unclear is the extent to which self-peptide/MHC class II (pMHCII)-specific T cells are deleted or become Foxp3 + regulatory T cells. We addressed this issue by characterizing a natural polyclonal pMHCII-specific CD4 + T-cell population in mice that either lacked or expressed the relevant antigen in a ubiquitous pattern. Mice expressing the antigen contained one-third the number of pMHCII-specific T cells as mice lacking the antigen, and the remaining cells exhibited low TCR avidity. In mice lacking the antigen, the pMHCII-specific T-cell population was dominated by phenotypically naive Foxp3− cells, but also contained a subset of Foxp3 + regulatory cells. Both Foxp3 − and Foxp3 + pMHCII-specific T-cell numbers were reduced in mice expressing the antigen, but the Foxp3 + subset was more resistant to changes in number and TCR repertoire. Therefore, thymic selection of self-pMHCII-specific CD4 + T cells results in incomplete deletion within the normal polyclonal repertoire, especially among regulatory T cells.ccording to clonal selection theory, self-reactive lymphocytes are deleted during development, thereby ensuring immunological tolerance to self tissues (1). In the case of T cells, this process occurs in the thymus where developing thymocytes with randomly generated T-cell antigen receptor (TCR) specificities are educated on an array of self-peptide/MHC (pMHC) ligands (2). In the simplest form of this model, thymocytes receiving strong TCR signals are deleted, thereby purging the repertoire of any cells with self-pMHC specificity. The significance of this mechanism of central tolerance has been substantiated by studies demonstrating that impairment of antigen presentation in the thymus can lead to autoimmunity (3, 4). Nevertheless, the clonal deletion rule is challenged by the wellknown observation that immunization with certain self-peptides can induce autoimmunity, indicating that at least some responsive self-pMHC-specific T cells routinely exist in the repertoire (5).Another intriguing exception to the clonal deletion rule is presented by regulatory T (Treg) cells, a suppressive subset of CD4 + T cells defined by expression of the Foxp3 transcription factor (6, 7). Whereas some Treg cells are induced from conventional T cells during immune responses (iTreg), most are socalled natural regulatory T (nTreg) cells, which arise directly in the thymus much like naive CD4 + T cells (8). Studies have shown that nTreg cells develop as a consequence of the type of high-affinity TCR-self-pMHCII interaction that was thought to cause clonal deletion (9). Moreover, extensive TCR sequencing studies of Treg and non-Treg populations have indicated that, whereas the specificities of these repertoires overlap, Treg cell specificity is biased toward self-pMHCII ligands (10, 11).These findings lead to the question of why some sel...

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“…“Natural” regulatory T (nTreg) cells that express the forkhead or winged helix transcription factor Foxp3 arise in the thymus, where they require high affinity T cell receptor (TCR) ligation by an agonist peptide-MHC complex for Foxp3 induction (Jordan et al, 2001; Relland et al, 2009). “Induced” Foxp3 + regulatory T (iTreg) cells can be generated from naïve, mature CD4 + “conventional” T (Tconv) cells during T cell activation by both TGF-β dependent and independent mechanisms (Chen et al, 2003; Schallenberg et al).…”

Section: Introductionmentioning

confidence: 99%

A Requisite Role for Induced Regulatory T Cells in Tolerance Based on Expanding Antigen Receptor Diversity

et al. 2011

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SUMMARY Although both natural and induced regulatory T (nTreg and iTreg) cells can enforce tolerance, the mechanisms underlying their synergistic actions have not been established. We examined the functions of nTreg and iTreg cells by adoptive transfer immunotherapy of newborn Foxp3-deficient mice. As monotherapy, only nTreg cells prevented disease lethality, but did not suppress chronic inflammation and autoimmunity. Provision of Foxp3-sufficient conventional T cells with nTreg cells reconstituted the iTreg pool and established tolerance. In turn, acute depletion of iTreg cells in rescued mice resulted in weight loss and inflammation. Whereas the transcriptional signatures of nTreg and in vivo derived iTreg cells were closely matched, there was minimal overlap in their T cell receptor (TCR) repertoires. Thus, iTreg cells are an essential non-redundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses.

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Affinity-Based Selection of Regulatory T Cells Occurs Independent of Agonist-Mediated Induction of Foxp3 Expression

Cited by 31 publications

References 72 publications

Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance

Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance

Quantitative impact of thymic selection on Foxp3 ⁺ and Foxp3 ⁻ subsets of self-peptide/MHC class II-specific CD4 ⁺ T cells

A Requisite Role for Induced Regulatory T Cells in Tolerance Based on Expanding Antigen Receptor Diversity

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Affinity-Based Selection of Regulatory T Cells Occurs Independent of Agonist-Mediated Induction of Foxp3 Expression

Cited by 31 publications

References 72 publications

Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance

Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance

Quantitative impact of thymic selection on Foxp3 + and Foxp3 − subsets of self-peptide/MHC class II-specific CD4 + T cells

A Requisite Role for Induced Regulatory T Cells in Tolerance Based on Expanding Antigen Receptor Diversity

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Quantitative impact of thymic selection on Foxp3 ⁺ and Foxp3 ⁻ subsets of self-peptide/MHC class II-specific CD4 ⁺ T cells