Dual receptor T cells extend the immune repertoire for foreign antigens

He, Xin; Janeway, Charles A.; Levine, Matthew H.; Robinson, Eve; Preston-Hurlburt, Paula; Viret, Christophe; Bottomly, Kim

doi:10.1038/ni751

Cited by 103 publications

(77 citation statements)

References 48 publications

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“…In one scenario, dual receptor T cells escape normal central tolerance mechanisms and are activated by self Ags in the periphery, predisposing to autoimmunity (39 -41). From another point of view, dual receptor T cells rescue nonfunctional T cells in the thymus and are activated by foreign Ag in the periphery, thereby expanding the T cell repertoire (42). Regardless of their role in immune responses, T cells bearing two receptors may not explain all the data, as non-TCR transgenic mice also showed partial tolerance at low Ag levels.…”

Section: Discussionmentioning

confidence: 96%

A Threshold for Central T Cell Tolerance to an Inducible Serum Protein

Haribhai

Engle

Meyer

et al. 2003

The Journal of Immunology

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We report an inducible system of self Ag expression that examines the relationship between serum protein levels and central T cell tolerance. This transgenic approach is based on tetracycline-regulated expression of a secreted form of hen egg lysozyme, tagged with a murine hemoglobin (Hb) epitope. In the absence of the tetracycline-regulated transactivator, serum levels of the chimeric protein are extremely low (≤0.1 ng/ml) and the mice show partial tolerance to both Hb(64–76) and lysozyme epitopes. In the presence of the transactivator, expression increases to 1.5 ng/ml and the mice are completely tolerant. Partial tolerance was further investigated by crossing these mice to strains expressing transgenic TCRs. At the lowest Ag levels, 3.L2tg T cells (specific for Hb(64–76)/I-Ek) escape the thymus and ∼10% of CD4+ splenocytes express the 3.L2 TCR. In contrast, 3A9 T cells (specific for hen egg lysozyme(46–61)/I-Ak) are completely eliminated by negative selection. These data define a tolerogenic threshold for negative selection of Ag-specific T cells by circulating self proteins that are 100-fold more sensitive than previously demonstrated. They suggest that partial tolerance at extremely low levels of self Ag exposure is the result of a restricted repertoire of responding T cells, rather than a simple reduction in precursor frequency; tolerogenic thresholds are T cell specific.

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Section: Discussionmentioning

confidence: 96%

A Threshold for Central T Cell Tolerance to an Inducible Serum Protein

Haribhai

Engle

Meyer

et al. 2003

The Journal of Immunology

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“…In-frame TCR Vγ 2 chains were supposed to form the second TCR, as described earlier (7,10). Most T cells follow the one-cell, one-receptor rule and express a single specificity of TCR.…”

Section: Discussionmentioning

confidence: 99%

“…This implies that only one amino acid was added in #067-restricted T-cell hybridomas, whereas two or three amino acids were added in #067-non restricted ones. In this study, we also suggested the possible presence of dual T-cell γδ receptors (TCR) (5,10,12), since some T-cell hybridomas exhibited dual in-frame transcripts of TCR Vγ 1 and Vγ 2.…”

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confidence: 99%

T‐Cell Receptor Variable γ Chain Gene Expression in the Interaction between Rat γδ‐Type T Cells and Heat‐Shock Protein 70‐Like Molecule

Ichinohe

Ichimiya

Kishi

et al. 2003

Microbiology and Immunology

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Abstract:We previously reported that rat T-cell receptor (TCR) V␦6 of T-cell hybridomas was preferentially involved in recognition of the cell surface-expressed 70 kDa rat heat-shock cognate (hsc70, a constitutively expressed member of the hsp 70 family) protein-like molecule (#067 molecule). In the present study, we analyzed usage of the TCR V␥ family of #067-restricted T-cell hybridomas. Our data indicated that most of these hybridomas expressed transcripts of TCR V␥1 and/or V␥2. However, some of the V␥2 transcripts were out-of-frame, suggesting that the TCR V␥1 family may be important for the recognition of #067-defined molecules. TCR V␥1 transcripts were detected in not only #067-restricted T-cell hybridomas, but #067-non restricted ones as well. However, V-J nucleotide sequences of #067-restricted and #067-non restricted T-cell hybridomas suggested that #067-restricted T-cell hybridomas showed limited insertion of nucleotide stretch as compared with #067-non restricted ones. In terms of amino acids, only one amino acid was added in #067-restricted T-cell hybridomas, whereas two or three amino acids were added in #067-non restricted ones. These data suggest that the heterodimer of the TCR relatively short stretch form of V␥1 molecule and TCR V␦6 may participate in recognition of the #067 molecule. Key words: Rat hsc70-like molecule, T-cell hybridomas, TCR V␥ usage 351Microbiol. Immunol., 47(5), [351][352][353][354][355][356][357] 2003 Abbreviations: DNT, CD4(−) and CD8(−) double-negative T cells; hsc70, 70 kDa heat-shock cognate protein; hsp, heat-shock protein; hsp70, 70 kDa heat-shock protein; RT-PCR, reverse transcription-polymerase chain reaction.

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“…Whatever the mechanism, some thymocytes that have escaped negative selection might leave the thymus for the periphery. Under physiological conditions, this may be of importance for T cells bearing two TCR␣ chains (46,47). Should one of these TCRs find an appropriate ligand for late positive selection, a positive signal could be generated that would counteract a negatively selecting signal transmitted via the other TCR on the same thymocyte.…”

Section: Cd8mentioning

confidence: 99%

Human CD4 Expression at the Late Single-Positive Stage of Thymic Development Supports T Cell Maturation and Peripheral Export in CD4-Deficient Mice

Boyer

Marodon

Cohen

et al. 2002

The Journal of Immunology

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Positive selection of developing thymocytes is initiated at the double-positive (DP) CD4+CD8+ stage of their maturation. Accordingly, expression of a human CD4 (hCD4) transgene beginning at the DP stage has been shown to restore normal T cell development and function in CD4-deficient mice. However, it is unclear whether later onset CD4 expression would still allow such a restoration. To investigate this issue, we used transgenic mice in which a hCD4 transgene is not expressed on DP, but only on single-positive cells. By crossing these animals with CD4-deficient mice, we show that late hCD4 expression supports the maturation of T cell precursors and the peripheral export of mature TCRαβ+ CD8− T cells. These results were confirmed in two different MHC class II-restricted TCR transgenic mice. T cells arising by this process were functional in the periphery because they responded to agonist peptide in vivo. Interestingly, thymocytes of these mice appeared refractory to peptide-induced negative selection. Together, these results indicate that the effect of CD4 on positive selection of class II-restricted T cells extends surprisingly late into the maturation process by a previously unrecognized pathway of differentiation, which might contribute to the generation of autoreactive T cells.

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Dual receptor T cells extend the immune repertoire for foreign antigens

Cited by 103 publications

References 48 publications

A Threshold for Central T Cell Tolerance to an Inducible Serum Protein

A Threshold for Central T Cell Tolerance to an Inducible Serum Protein

T‐Cell Receptor Variable γ Chain Gene Expression in the Interaction between Rat γδ‐Type T Cells and Heat‐Shock Protein 70‐Like Molecule

Human CD4 Expression at the Late Single-Positive Stage of Thymic Development Supports T Cell Maturation and Peripheral Export in CD4-Deficient Mice

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