Highly Restricted T Cell Repertoire Shaped by a Single Major Histocompatibility Complex–Peptide Ligand in the Presence of a Single Rearranged T Cell Receptor β Chain

Fukui, Yoshihiro; Hashimoto, Osamu; Inayoshi, Ayumi; Gyotoku, Takahiro; Sano, Tetsuro; Koga, Toru; Gushima, Toshifumi; Sasazuki, Takehiko

doi:10.1084/jem.188.5.897

Cited by 26 publications

(21 citation statements)

References 67 publications

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“…However, in light of the present results that CD4 ϩ T cell differentiation is remarkably different between two sets of transgenic TKO mouse lines expressing the I-A b molecule covalently bound to p 60K or p E␣ at comparable levels in the thymus, it seems unlikely that non-E␣ peptides select the majority of CD4 ϩ T cells in these lines. Therefore, although it is clear that T cell repertoire shaped by I-A b -p E␣ complex does not include all of the TCR specificity seen in normal mice (17,21), self-peptides like p E␣ with uncharged and relatively small amino acid residues at TCR contacts, especially at P5, may serve as ''superselectors'' when they are expressed at an appropriate level in the thymus (13). In contrast, I-A b -p 60K complex selects only small numbers of CD4 ϩ T cells and shapes less diverse T cell repertoire, suggesting that the substitution from leucine to lysine at P5 residue results in requirement for more stringent TCRpeptide interactions to survive positive selection directed by this ligand.…”

Section: Discussionmentioning

confidence: 99%

“…Details have been described elsewhere (21). Briefly, total cellular RNA extracted from the sorted CD4 ϩ CD8 Ϫ thymocytes was primed with C␣-specific antisense oligonucleotide for cDNA synthesis.…”

Section: Methodsmentioning

confidence: 99%

“…With the use of in vitro and in vivo experimental systems, it was shown that limited numbers of self-peptides bound to a given MHC molecule fail to support positive selection of CD8 ϩ or CD4 ϩ T cells expressing a transgenic TCR␣␤ that are selected by the same MHC molecule with a normal array of self-peptides (14)(15)(16)(17)(18)(19). In addition, CD4 ϩ T cells selected to mature on such MHC class II molecules were shown to express highly restricted TCR␣ chains in the presence of a single rearranged TCR␤ (20,21). Thus, it is clear that specific recognition of self-peptides by TCRs could be involved during the process of positive selection.…”

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Diversity of T cell repertoire shaped by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor contact

Fukui

Oono

Cabaniols

et al. 2000

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

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T cell differentiation in the thymus is driven by positive selection through the interaction of ␣␤ T cell receptors (TCRs) with selfpeptides bound to self-major histocompatibility complex molecules, yet the influence of the peptide sequence on this process remains unknown. To address this issue, we have compared CD4 ؉ T cell differentiation between two sets of mouse lines in which MHC class II I-A b molecules are occupied with either E␣ chainderived peptide ( pE␣) or its variant, p60K, with one amino acid substitution from leucine to lysine at P5 residue of TCR contacts. Here, we show that despite the comparable expression of I-A bpeptide complex in the thymus, this substitution from leucine to lysine affects efficiency of positive selection, resulting in extremely small numbers of CD4 ؉ T cells to be selected to mature on I-A b -p60K complex. Furthermore, we show that, although I-A b -pE␣ complex selects diverse T cells, T cell repertoire shaped by I-A b -p60K complex is markedly constrained. Our findings thus suggest that positive selection is both specific and degenerate, depending on the amino acid residues at TCR contacts of the selecting self-peptides.A lthough the diversity of ␣␤ T cell receptors (TCRs) theoretically reaches 10 15 by random rearrangement of five gene segments (V␣, J␣, V␤, D␤, and J␤) and random nucleotide addition (1), mature T cells express highly selected TCRs in that they exhibit tolerance to self-antigenic peptides and restriction by self-MHC molecules. This mainly results from two reciprocal selection processes, positive and negative selection, acting during T cell development in the thymus. Positive selection is the process that induces the differentiation of CD4 ϩ CD8 ϩ immature thymocytes into CD4 Ϫ CD8 ϩ or CD4 ϩ CD8 Ϫ mature thymocytes only when their TCRs recognize self-MHC class I or class II molecules with sufficient, albeit weak, affinity and ensures that the specificity of mature T cell repertoire is directed against antigenic peptides bound to self-MHC molecules. On the other hand, negative selection plays a central role in tolerance induction by eliminating immature thymocytes bearing TCRs specific for self-peptides bound to self-MHC molecules.Since the discovery that positive selection is influenced by the substitutions at amino acid residues of MHC molecules positioned toward the peptide-binding groove (2-5), the role of self-peptides in positive selection has been the subject of considerable debate. This was first directly addressed for CD8 ϩ T cells using fetal thymic organ cultures derived from mutant mouse strains where a particular MHC class I-peptide complex is expressed by exogenously adding a given peptide to the culture (6-8). Subsequently, several groups developed in vivo experimental system focusing on the role of self-peptides in positive selection of CD4 ϩ T cells by creating mouse strains in which all or a large fraction of the MHC class II molecules are occupied with a single peptide (9-13). With the use of in vitro and in vivo experimental systems, it wa...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Diversity of T cell repertoire shaped by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor contact

Fukui

Oono

Cabaniols

et al. 2000

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

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“…In a distinct TCR ␤-chain Tg system, both V and J gene segment usages of the companion ␣-chain were significantly biased in mature T cells (19). The impact of a TCR ␤-chain transgene on the ␣-chain repertoire was also observed in mice expressing a single peptide:MHC class II complex unrelated to the parental TCR; both the V␣ usage and the amino acid composition of the CDR3 loop were significantly influenced (20). Finally, mice transgenic for the ␤-chain of the MCC88 -103:I-E k complex-specific 5C.C7 ␣␤ TCR were analyzed using MCC88 -103:I-E k tetramers, which stain 95% of 5C.C7 ␣␤ TCR Tg thymocytes (15).…”

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confidence: 99%

A NK1.1+ Thymocyte-Derived TCR β-Chain Transgene Promotes Positive Selection of Thymic NK1.1+ αβ T Cells

Viret

Lantz

et al. 2000

The Journal of Immunology

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As a consequence of the peptide specificity of intrathymic positive selection, mice transgenic for a rearranged TCR β-chain derived from conventional αβ T lymphocytes frequently carry mature T cells with significant skewing in the repertoire of the companion α-chain. To assess the generality of such an influence, we generated transgenic (Tg) mice expressing a β-chain derived from nonclassical, NK1.1+ αβ T cells, the thymus-derived, CD1.1-specific DN32H6 T cell hybridoma. Results of the sequence analysis of genomic DNA from developing DN32H6 β Tg thymocytes revealed that the frequency of the parental α-chain sequence, in this instance the Vα14-Jα281 canonical α-chain, is specifically and in a CD1.1-dependent manner, increased in the postselection thymocyte population. In accordance, we found phenotypic and functional evidence for an increased frequency of thymic, but interestingly not peripheral, NK1.1+ αβ T cells in DN32H6 β Tg mice, possibly indicating a thymic determinant-dependent maintenance. Thus, in vivo expression of the rearranged TCR β-chain from a thymus-derived NK1.1+ Vα14+ T cell hybridoma promotes positive selection of thymic NK1.1+ αβ T cells. These observations indicate that the strong influence of productive β-chain rearrangements on the TCR sequence and specificity of developing thymocytes, which operates through positive selection on self-determinants, applies to both classical and nonclassical αβ T cells and therefore represents a general phenomenon in intrathymic αβ T lymphocyte development.

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“…Earlier, we reported on transgenic mouse lines that have been developed by introducing the gene encoding the I-Aβ b chain covalently bound to Eα chain-derived peptide (Eα52-68) into mice lacking I-Aβ b , invariant chain, and β2-microglobulin (TKO mice) (22)(23)(24). Thus far, no evidence has been provided that the I-A b molecules expressed in such mice present self-or foreign antigenic peptides other than Eα52-68 to T cells (22,25,26), suggesting that I-A b -Eα52-68 complex is the only MHC-peptide complex expressed in these mice.…”

Section: Introductionmentioning

confidence: 99%

Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide

Oono¹,

Fukui²,

Masuko³

et al. 2001

J. Clin. Invest.

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Organ-specific autoimmune diseases have been postulated to be the result of T cell response against organ-specific self-peptides bound to MHC molecules. Contrary to this paradigm, we report here that transgenic mice lacking MHC class I expression and expressing an MHC class II I-A b molecule that presents only a single peptide (Eα52-68) spontaneously develops peripheral nervous system-specific autoimmune disease with many of the histopathological features found in experimental allergic neuritis. Reciprocal bone marrow chimeras produced using susceptible and resistant lines revealed that bone marrow-derived cells determined disease susceptibility. While the expression of the I-A b -Eα52-68 complex in the periphery was readily detectable in both lines, its expression on thymic dendritic cells responsible for tolerance induction was markedly lower in the susceptible line than in the resistant line. Consistent with this, CD4 + T cells that can be activated by the I-A b -Eα52-68 complex were found in the susceptible line, but not in the resistant line. Such CD4 + T cells conferred the disease to the resistant line by adoptive transfer, and administration of Ab specific for the I-A b -Eα52-68 complex inhibited disease manifestation in the susceptible line. These results indicate that disease development involves systemic T cell reactivity to I-A b -Eα52-68 complex, probably caused by incomplete negative thymocyte selection.

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Highly Restricted T Cell Repertoire Shaped by a Single Major Histocompatibility Complex–Peptide Ligand in the Presence of a Single Rearranged T Cell Receptor β Chain

Cited by 26 publications

References 67 publications

Diversity of T cell repertoire shaped by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor contact

Diversity of T cell repertoire shaped by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor contact

A NK1.1+ Thymocyte-Derived TCR β-Chain Transgene Promotes Positive Selection of Thymic NK1.1+ αβ T Cells

Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide

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