Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Kersh, Gilbert J.; Engle, Deborah L.; Williams, Calvin B.; Allen, Paul M.

doi:10.4049/jimmunol.164.11.5675

Cited by 10 publications

(6 citation statements)

References 46 publications

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“…The CD4 + CD8 + , double positive (DP) compartment was significantly depleted, which was accompanied by a significant increase in CD4 − CD8 + (CD8SP) cells. These observations are consistent with previous data (51, 52). Although the size of the CD4SP compartment remained unchanged, the proportion and number of Foxp3 + cells increased in direct relation to the N72 peptide dose and reached a maximum at a concentration of 1 μM (Figure 4B).…”

Section: Resultssupporting

confidence: 94%

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

Relland

Mishra

Haribhai

et al. 2009

The Journal of Immunology

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Natural regulatory T (nTreg) cells recognize self-peptides with high affinity, yet the understanding of how affinity influences their selection in the thymus is incomplete. We use altered peptide ligands in transgenic mice and in organ culture to create thymic environments spanning a broad range of ligand affinity. We demonstrate that the nTreg TCR repertoire is shaped by affinity-based selection, similar to conventional T cells. The effect of each ligand on the two populations is distinct, consistent with early nTreg cell lineage specification. Foxp3 expression is an independent process that does not rely on “high affinity” binding per se, but requires a high-potency agonistic interaction for its induction. The timing of ligand exposure, TGFβ signaling, and the organization of the thymic architecture are also important. The development of nTreg cells is therefore a multistep process in which ligand affinity, potency, and timing of presentation all play a role in determining cell fate.

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Section: Resultssupporting

confidence: 94%

“…NTOC with T72 peptide (weak agonist) treatment also induced Foxp3 expression, although it was markedly lower. In contrast, the antagonist I72 peptide, which is sufficient to induce negative selection of T conv cells (Figure 1D, (22, 51)), did not result in the upregulation of Foxp3 (Figure 4C). …”

Section: Resultsmentioning

confidence: 92%

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

Relland

Mishra

Haribhai

et al. 2009

The Journal of Immunology

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“…Together, these data support the conclusion that even peptides possessing weak affinities for MHC class II molecules can be effective inducers of central tolerance provided that they are displayed in the thymus. These results are consistent with those obtained by Allen and colleagues, who demonstrated that certain antagonistic peptides could negatively select CD4 ϩ T cells (18). In addition, the ability of Ac1-9 to negatively select Ac1-9-specific T cells has been confirmed by Lafaille and colleagues (personal communication).…”

Section: Figsupporting

confidence: 91%

Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC

Maverakis

Beech

Stevens

et al. 2003

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

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It is not clear why the N-terminal autoantigenic determinant of myelin basic protein (MBP), Ac1-9, is dominant in the B1O.PL (H-2 u ) mouse, given its weak I-A u -MHC binding affinity. Similarly, how do high-affinity T cells specific for this determinant avoid negative selection? Because the MBP:1-9 sequence is embryonically expressed uniquely in the context of Golli-MBP, determinants were sought within the contiguous N-terminal ''Golli'' region that could out-compete MBP:1-9 for MHC binding, and thereby prevent negative selection of the public response to Ac1-9, shown here to be comprised of a V␤8.2J␤2.7 and a V␤8.2J␤2.4 expansion. Specifically, we demonstrate that Ac1-9 itself can be an effective inducer of central tolerance induction; however, in the context of Golli-MBP, Ac1-9 is flanked by determinants which prevent its display to autoreactive T cells. Our data support competitive capture as a means of protecting high-affinity, autoreactive T cells from central tolerance induction.

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“…3A), whereas more CD4 than CD8 T cells are normally generated in vivo . This tendency has been observed in FTOC (unpublished data and 58–61). When fetal thymi were treated with MCD and cultured in normal FBS, the percentage of CD4 T cells decreased, while that of CD8 T cells increased (Fig.…”

Section: Resultssupporting

confidence: 70%

Lipid‐mediated presentation of MHC class II molecules guides thymocytes to the CD4 lineage

et al. 2009

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Previous studies on the MHC class-specific differentiation of CD4 + CD8 + thymocytes into CD4 + and CD8 + T cells have focused on the role of coreceptor molecules. However, CD4 and CD8 T cells develop according to their MHC class specificities even in these mice lacking coreceptors. This study investigated the possibility that lineage is determined not only by coreceptors, but is also guided by the way how MHC molecules are presented. MHC class II molecules possess a highly conserved Cys in their transmembrane domain, which is palmitoylated and thereby associates with lipid rafts, whereas neither palmitoylation nor raft association was observed with MHC class I molecules. The generation of CD4 T cells was impaired and that of CD8 T cells was augmented when the rafts on the thymic epithelial cells were disrupted. This was due to the conversion of MHC class II-specific thymocytes from the CD4 lineage to CD8. The ability of I-A d molecule to associate with rafts was lost when its transmembrane Cys was replaced. The development of DO11.10 thymocytes recognizing this mutant I-A dm was converted from CD4 to CD8. These results suggest that the CD4 lineage commitment is directed by the raft-associated presentation of MHC class II molecules.Key words: CD4 T cell . Lipid rafts . MHC class II molecule . Thymic selection Supporting Information available online IntroductionThe ab T cells differentiate from immature CD4 + CD8 + doublepositive (DP) thymocytes to mature CD4 + and CD8 + singlepositive (SP) T cells in the thymus. This differentiation is achieved through TCR signaling that follows the engagement with self-MHC peptide complexes. The resulting CD4 and CD8 T cells possess MHC class II-specific TCR and MHC class I-specific TCR, respectively, which is consistent with MHC binding specificities of the coreceptors they express. The exact mechanism by which the DP thymocytes are committed to the appropriate T-cell lineage is not yet clear.Earlier investigations on CD4 versus CD8 lineage commitment in the thymus have focused on the roles played by coreceptor molecules. Robey et al. [1] proposed the presence of an instructive signal for CD8 T-cell development and demonstrated that constitutive CD8 expression induces substantial increase in the CD8 lineage commitment, while it has no apparent effect on CD4 96lineage commitment. The instructive model is supported for CD4 T-cell development as well, by experiments in which transgenic chimeric molecules consisting of the CD8a extracellular domain and transmembrane (TM) of CD4 or CD8 and the cytoplasmic domain of CD4 were shown to induce CD4 T cells expressing MHC class I-specific TCR [2,3]. The identification of a defect that impairs only CD4 T-cell development also supports the instructive model [4]. These observations collectively suggest that the coreceptors instruct thymocytes to differentiate into either CD4 or CD8 T cells by initiating qualitatively distinct signals. However, the functional differences between the CD4 and CD8 are mostly quantitative, i.e. more Lck molecu...

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Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Cited by 10 publications

References 46 publications

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

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

Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC

Lipid‐mediated presentation of MHC class II molecules guides thymocytes to the CD4 lineage

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