Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage

Robey, Ellen; Fowlkes, B. J.; Gordon, Jon W.; Kioussis, Dimitris; Boehmer, Harald von; Ramsdell, Fred; Axel, Richard

doi:10.1016/0092-8674(91)90212-h

Cited by 206 publications

(119 citation statements)

References 37 publications

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“…Models have proposed that coengagement of TCR and coreceptor to MHC conveys lck to activate downstream signaling. The developmental link between MHC specificity and coreceptor expression as shown by the analysis of TCR-Tg mice has been explained by an instructional model (8,9). However, the recent findings demonstrating the existence of coreceptor transitional cells, CD4 ϩ CD8 low in class II-deficient (11) and CD4 low CD8 ϩ in class I-deficient mice (12), is inconsistent with the instructional model and has been offered as an evidence for a stochastic model, and these populations are thought to be lineage-committed intermediates in positive selection.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have indicated that CD8 lineage commitment is dependent on the interaction of the TCR with MHC class I molecules and may also involve CD8-dependent signals (8,13). In ␤ 2 m-deficient mice, the expression of MHC class I was extremely reduced and positive selection of CD8 T cells was impaired (26).…”

Section: Mhc Class I-independent Cd8 Lineage Commitmentmentioning

confidence: 99%

“…Two models had proposed to explain the development of T cells bearing matched TCR and coreceptor specificities. An instructive model proposes that MHC restriction of the TCR determines lineage commitment (8,9). T cells expressing MHC class I-or class II-restricted TCR down-regulate CD4 or CD8, respectively.…”

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confidence: 99%

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The Quantity of TCR Signal Determines Positive Selection and Lineage Commitment of T Cells

Watanabe

Arase

Onodera

et al. 2000

The Journal of Immunology

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It is generally accepted that the avidity of TCR for self Ag/MHC determines the fate of immature thymocytes. However, the contribution of the quantity of TCR signal to T cell selection has not been well established, particularly in vivo. To address this issue, we analyzed DO-TCR transgenic CD3ζ-deficient (DO-Tg/ζKO) mice in which T cells have a reduced TCR on the cell surface. In DO-Tg/ζKO mice, very few CD4 single positive (SP) thymocytes developed, indicating that the decrease in TCR signaling resulted in a failure of positive selection of DO-Tg thymocytes. Administration of the peptide Ag to DO-Tg/ζKO mice resulted in the generation of functional CD4 SP mature thymocytes in a dose-dependent manner, and, unexpectedly, DO-Tg CD8 SP cells emerged at lower doses of Ag. TCR signal-dependent, sequential commitment from CD8+ SP to CD4+ SP was also shown in a class I-restricted TCR-Tg system. These in vivo analyses demonstrate that the quantity of TCR signal directly determines positive and negative selection, and further suggest that weak signal directs positively selected T cells to CD8 lineage and stronger signal to CD4 lineage.

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Section: Discussionmentioning

confidence: 99%

Section: Mhc Class I-independent Cd8 Lineage Commitmentmentioning

confidence: 99%

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The Quantity of TCR Signal Determines Positive Selection and Lineage Commitment of T Cells

Watanabe

Arase

Onodera

et al. 2000

The Journal of Immunology

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“…The effects of CD4 and CD8 phenotypes are examples of the former 2,3 while useful insights into T cell development have been gained from rearranged T cell receptor transgenics as examples of the latter. 4 In contrast, the existence of genetically determined natural variation in levels of T cell subpopulations in mice and humans has received little attention. Studies in mice first showed that T cell subset representation was strain dependent and therefore under genetic control.…”

Section: Introductionmentioning

confidence: 99%

Genetic influence on peripheral blood T lymphocyte levels

Ahmadi

Norman

et al. 2000

Genes Immun

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T lymphocytes are a major component of the adaptive immune system. CD4 positive T cell subpopulations regulate B cell and macrophage effector function while CD8 positive T cells are largely responsible for anti-viral cytotoxic activity. The degree of natural variation in the levels and ratios of the various T cell subpopulations is a possible risk factor for the development of autommune disease, infectious disease and cancer. There is some evidence from studies of inbred strains of mice and humans which suggests that variation in T cell subpopulations is genetically influenced. However, family studies alone cannot distinguish between common environmental and shared genetic influences and provide less robust estimates of the heritability than twin studies. To comprehensively examine genetic influences on a selection of important T cell phenotypes, we investigated variation in levels of total lymphocytes, CD3 + , CD4 + , CD8 + , CD3 + CD4 + , CD3 + CD8 + lymphocytes and in CD4:CD8 ratio as a proportion of lymphocytes and of T cells using the classical twin model approach. Healthy female twin pairs were sampled from the St. Thomas' UK Adult Twin Registry. A maximum of 103 monozygotic (MZ) and 186 dizygotic (DZ) twins aged 18-80 years participated in the study. Whole blood samples were analysed for T cell subsets by flow cytometry. The relative genetic contribution to these phenotypes was estimated using a variance components model-fitting approach. Heritability estimates were calculated of 65% for CD4:CD8 T cell and lymphocyte ratios, around 50% for absolute lymphocyte, CD3 + and CD4 + counts, and 56% for CD8 + numbers. Unique (rather than shared) familial environment explains the remainder of the variance. Genetic factors have a major influence on the variation in peripheral T cell subset numbers. Polymorphism dictating such variation should be taken into account when assessing risk factors for T cell immune-mediated disease with a genetic background. Genes and Immunity (2000) 1, 423-427.

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“…CD8tg is a C57BL/6 strain overexpressing CD8␤ and CD8␣ under the control of the CD2 promoter (29). ␤2M 0 is a 129 ϫ C57BL/6 strain with a targeted disruption of ␤ 2 -microglobulin (␤ 2 m) on both chromosomes (30).…”

Section: Micementioning

confidence: 99%

Positive Selection Is Limited by Available Peptide-Dependent MHC Conformations

Stefanski

Jameson

Hogquist

2000

The Journal of Immunology

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Recent data suggest that the diversity of self peptides presented in the thymus during development contributes to positive selection of a diverse T cell repertoire. We sought to determine whether a previously defined “hole in the immunological repertoire” could be explained by the absence of an appropriate selecting self peptide. The repertoire defect in question is the inability of bm8 mice to make an H-2K-restricted response to OVA. Like other OVA-specific, H-2K-restricted receptors, OT-I-transgenic T cells are not positively selected in bm8 mice. Using criteria we had previously established for identifying positive selection ligands, we found peptides that could restore positive selection of OT-I thymocytes in bm8 mice. Thus, the T cell repertoire can be limited by a requirement for specific self peptides during development. Data with MHC-specific Abs suggested that peptides might be able to force MHC residues to adopt different conformations in Kb vs Kbm8. This shows that peptides can potentially contribute to ligand diversity both directly (via variability in the solvent-exposed side chains) and indirectly (through their effect on the MHC conformation). Our data support a model where self peptide diversity allows selection of T cells specific for a broad range of MHC conformations.

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Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage

Cited by 206 publications

References 37 publications

The Quantity of TCR Signal Determines Positive Selection and Lineage Commitment of T Cells

The Quantity of TCR Signal Determines Positive Selection and Lineage Commitment of T Cells

Genetic influence on peripheral blood T lymphocyte levels

Positive Selection Is Limited by Available Peptide-Dependent MHC Conformations

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