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The CD3-gammadeltaepsilon and CD3-zeta/eta modules are each essential for allelic exclusion at the T cell receptor beta locus but are both dispensable for the initiation of V to (D)J recombination at the T cell receptor-beta, -gamma, and -delta loci.

Ardouin L, Ismaili J, Malissen B, Malissen M - J. Exp. Med. (1998)

Bottom Line: The pre-T cell receptor (TCR) associates with CD3-transducing subunits and triggers the selective expansion and maturation of T cell precursors expressing a TCR-beta chain.Furthermore, using mutant mice lacking both the CD3-epsilon and CD3-zeta/eta genes, we established that the CD3 gene products are dispensable for the onset of V to (D)J recombination (V, variable; D, diversity; J, joining) at the TCR-beta, TCR-gamma, and TCR-delta loci.Thus, the CD3 components are differentially involved in the sequential events that make the TCR-beta locus first accessible to, and later insulated from, the action of the V(D)J recombinase.

View Article: PubMed Central - PubMed

Affiliation: Centre d'Immunologie Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique de Marseille-Luminy, Case 906, 13288 Marseille Cedex 9, France.

ABSTRACT
The pre-T cell receptor (TCR) associates with CD3-transducing subunits and triggers the selective expansion and maturation of T cell precursors expressing a TCR-beta chain. Recent experiments in pre-Talpha chain-deficient mice have suggested that the pre-TCR may not be required for signaling allelic exclusion at the TCR-beta locus. Using CD3-epsilon- and CD3-zeta/eta-deficient mice harboring a productively rearranged TCR-beta transgene, we showed that the CD3-gammadeltaepsilon and CD3-zeta/eta modules, and by inference the pre-TCR/CD3 complex, are each essential for the establishment of allelic exclusion at the endogenous TCR-beta locus. Furthermore, using mutant mice lacking both the CD3-epsilon and CD3-zeta/eta genes, we established that the CD3 gene products are dispensable for the onset of V to (D)J recombination (V, variable; D, diversity; J, joining) at the TCR-beta, TCR-gamma, and TCR-delta loci. Thus, the CD3 components are differentially involved in the sequential events that make the TCR-beta locus first accessible to, and later insulated from, the action of the V(D)J recombinase.

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Vβ to DβJβ rearrangements are not affected in CD3-εΔ5/Δ5  CD3-ζ/η−/− double mutant mice. The relative levels of TCR-β rearrangements found in εΔ5/Δ5ζ/η+/+, ε+/+ζ/η−/−, and εΔ5/Δ5ζ/η−/− thymocytes were determined as described in the legend of Fig. 4.
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Figure 7: Vβ to DβJβ rearrangements are not affected in CD3-εΔ5/Δ5 CD3-ζ/η−/− double mutant mice. The relative levels of TCR-β rearrangements found in εΔ5/Δ5ζ/η+/+, ε+/+ζ/η−/−, and εΔ5/Δ5ζ/η−/− thymocytes were determined as described in the legend of Fig. 4.

Mentions: The molecular mechanisms regulating the development of B cells and α/β T cells display striking similarities (see review in references 33 and 34). For instance, pre–B cells express a B cell analogue of the pre–T cell receptor called the pre–B cell receptor. The pre–B cell receptor associates with Igα/Igβ transducing subunits and triggers both the selective amplification/maturation of IgH+ pre–B cells and establishement of allelic exclusion at the IgH locus (34). Igβ-deficient mice show a complete block in B cell development at a stage corresponding to the CD44−/lowCD25+ stage of T cell development (35). Interestingly, VH to DHJH rearrangements were found to be severely reduced in Igβ-deficient mice, whereas DH to JH rearrangements proceeded normally. This indicated that Ig-β may play an important regulatory role in the onset of VH to DHJH recombination. When bred separately, the CD3-εΔ5 and CD3-ζ/η mutations had no discernible effect on the occurrence and extent of Vβ to DβJβ recombination (Figs. 4 and 5). Therefore, the V to DJ recombination events affecting TCR-β and IgH loci may be subjected to distinct regulatory signals. It is also possible, however, that the CD3-ε and CD3-ζ/η chains play redundant regulatory roles in the onset of Vβ to DβJβ recombination. To address this question, mice lacking both proteins were derived from a F2 intercross between CD3-εΔ5/Δ5 and CD3-ζ/η−/− mice. As shown in Fig. 6, mice lacking both CD3-ε and CD3-ζ/η chains had thymuses the size and surface phenotype of which closely resemble those found in parental CD3-εΔ5/Δ5 mice (Fig. 7, compare the CD4/CD8 and CD44/CD25 profiles of panels εΔ5/Δ5/ζ/η+/+ and εΔ5/Δ5/ ζ/η−/−). Interestingly, ε+/+ ζ/η−/− and ε+/Δ5 ζ/η−/− thymuses displayed markedly different CD4/CD8 phenotypes, the latter closely resembling in size and composition those developing in εΔ5/Δ5 ζ/η−/− double-mutant mice (Fig. 6). Thus, in the absence of CD3-ζ/η chains, the CD3-εΔ5 mutation manifests a clear gene-dosage effect, suggesting that in a CD3-ζ/η–less context, it is the CD3-ε subunits that limit the number of pre-TCR subcomplexes available for driving the transition to the DP stage.


The CD3-gammadeltaepsilon and CD3-zeta/eta modules are each essential for allelic exclusion at the T cell receptor beta locus but are both dispensable for the initiation of V to (D)J recombination at the T cell receptor-beta, -gamma, and -delta loci.

Ardouin L, Ismaili J, Malissen B, Malissen M - J. Exp. Med. (1998)

Vβ to DβJβ rearrangements are not affected in CD3-εΔ5/Δ5  CD3-ζ/η−/− double mutant mice. The relative levels of TCR-β rearrangements found in εΔ5/Δ5ζ/η+/+, ε+/+ζ/η−/−, and εΔ5/Δ5ζ/η−/− thymocytes were determined as described in the legend of Fig. 4.
© Copyright Policy
Related In: Results  -  Collection

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Figure 7: Vβ to DβJβ rearrangements are not affected in CD3-εΔ5/Δ5 CD3-ζ/η−/− double mutant mice. The relative levels of TCR-β rearrangements found in εΔ5/Δ5ζ/η+/+, ε+/+ζ/η−/−, and εΔ5/Δ5ζ/η−/− thymocytes were determined as described in the legend of Fig. 4.
Mentions: The molecular mechanisms regulating the development of B cells and α/β T cells display striking similarities (see review in references 33 and 34). For instance, pre–B cells express a B cell analogue of the pre–T cell receptor called the pre–B cell receptor. The pre–B cell receptor associates with Igα/Igβ transducing subunits and triggers both the selective amplification/maturation of IgH+ pre–B cells and establishement of allelic exclusion at the IgH locus (34). Igβ-deficient mice show a complete block in B cell development at a stage corresponding to the CD44−/lowCD25+ stage of T cell development (35). Interestingly, VH to DHJH rearrangements were found to be severely reduced in Igβ-deficient mice, whereas DH to JH rearrangements proceeded normally. This indicated that Ig-β may play an important regulatory role in the onset of VH to DHJH recombination. When bred separately, the CD3-εΔ5 and CD3-ζ/η mutations had no discernible effect on the occurrence and extent of Vβ to DβJβ recombination (Figs. 4 and 5). Therefore, the V to DJ recombination events affecting TCR-β and IgH loci may be subjected to distinct regulatory signals. It is also possible, however, that the CD3-ε and CD3-ζ/η chains play redundant regulatory roles in the onset of Vβ to DβJβ recombination. To address this question, mice lacking both proteins were derived from a F2 intercross between CD3-εΔ5/Δ5 and CD3-ζ/η−/− mice. As shown in Fig. 6, mice lacking both CD3-ε and CD3-ζ/η chains had thymuses the size and surface phenotype of which closely resemble those found in parental CD3-εΔ5/Δ5 mice (Fig. 7, compare the CD4/CD8 and CD44/CD25 profiles of panels εΔ5/Δ5/ζ/η+/+ and εΔ5/Δ5/ ζ/η−/−). Interestingly, ε+/+ ζ/η−/− and ε+/Δ5 ζ/η−/− thymuses displayed markedly different CD4/CD8 phenotypes, the latter closely resembling in size and composition those developing in εΔ5/Δ5 ζ/η−/− double-mutant mice (Fig. 6). Thus, in the absence of CD3-ζ/η chains, the CD3-εΔ5 mutation manifests a clear gene-dosage effect, suggesting that in a CD3-ζ/η–less context, it is the CD3-ε subunits that limit the number of pre-TCR subcomplexes available for driving the transition to the DP stage.

Bottom Line: The pre-T cell receptor (TCR) associates with CD3-transducing subunits and triggers the selective expansion and maturation of T cell precursors expressing a TCR-beta chain.Furthermore, using mutant mice lacking both the CD3-epsilon and CD3-zeta/eta genes, we established that the CD3 gene products are dispensable for the onset of V to (D)J recombination (V, variable; D, diversity; J, joining) at the TCR-beta, TCR-gamma, and TCR-delta loci.Thus, the CD3 components are differentially involved in the sequential events that make the TCR-beta locus first accessible to, and later insulated from, the action of the V(D)J recombinase.

View Article: PubMed Central - PubMed

Affiliation: Centre d'Immunologie Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique de Marseille-Luminy, Case 906, 13288 Marseille Cedex 9, France.

ABSTRACT
The pre-T cell receptor (TCR) associates with CD3-transducing subunits and triggers the selective expansion and maturation of T cell precursors expressing a TCR-beta chain. Recent experiments in pre-Talpha chain-deficient mice have suggested that the pre-TCR may not be required for signaling allelic exclusion at the TCR-beta locus. Using CD3-epsilon- and CD3-zeta/eta-deficient mice harboring a productively rearranged TCR-beta transgene, we showed that the CD3-gammadeltaepsilon and CD3-zeta/eta modules, and by inference the pre-TCR/CD3 complex, are each essential for the establishment of allelic exclusion at the endogenous TCR-beta locus. Furthermore, using mutant mice lacking both the CD3-epsilon and CD3-zeta/eta genes, we established that the CD3 gene products are dispensable for the onset of V to (D)J recombination (V, variable; D, diversity; J, joining) at the TCR-beta, TCR-gamma, and TCR-delta loci. Thus, the CD3 components are differentially involved in the sequential events that make the TCR-beta locus first accessible to, and later insulated from, the action of the V(D)J recombinase.

Show MeSH