Tracing lymphopoiesis with the aid of a pTα-controlled reporter gene

Gounari, Fotini; Aifantis, Iannis; Martin, Colin H.; Fehling, Hans-Joerg; Hoeflinger, Sonja; Leder, Philip; Boehmer, Harald von; Reizis, Boris

doi:10.1038/ni778

Cited by 83 publications

(78 citation statements)

References 42 publications

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“…Interestingly, the endogenous TCRb locus was allelically excluded in such cd cells in all three TCRb Tg lines, and this allelic exclusion could be reversed in the absence of pTa. These data provide direct functional evidence that pTa is expressed in precursors of cd cells, confirming and extending earlier studies of ic pTa [6] and pTa reporter gene expression [20] in immature DN3 thymocytes. Thus, models of ab/cd lineage commitment that propose a restricted expression or function of pTa in the ab lineage [34,35] are clearly oversimplified.…”

Section: Discussionsupporting

confidence: 88%

“…Previous studies using pTa ic staining [6], single-cell PCR [19] and reporter mice [20] are consistent with the possibility that most DN3 thymocytes, which have recently been shown to contain a very small subset of cd precursors [21], express pTa. However, no functional evidence for the presence of pTa in cd precursors has been reported.…”

Section: Tcrb Transgenes Mediate Pta-dependent Allelic Exclusion In Csupporting

confidence: 60%

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A critical lineage‐nonspecific role for pTα in mediating allelic and isotypic exclusion in TCRβ‐transgenic mice

Ferrero¹,

Grosjean²,

Fiorini³

et al. 2007

Eur J Immunol

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Although it is well established that early expression of TCRb transgenes in the thymus leads to efficient inhibition of both endogenous TCRb and TCRc rearrangement (also known as allelic and "isotypic" exclusion, respectively) the role of pTa in these processes remains controversial. Here, we have systematically re-evaluated this issue using three independent strains of TCRb-transgenic mice that differ widely in transgene expression levels, and a sensitive intracellular staining assay that detects endogenous TCRVb expression in individual immature thymocytes. In the absence of pTa, both allelic and isotypic exclusion were reversed in all three TCRb-transgenic strains, clearly demonstrating a general requirement for pre-TCR signaling in the inhibition of endogenous TCRb and TCRc rearrangement. Both allelic and isotypic exclusion were pTa dose dependent when transgenic TCRb levels were subphysiological. Moreover, pTa-dependent allelic and isotypic exclusion occurred in both ab and cd T cell lineages, indicating that pre-TCR signaling can potentially be functional in cd precursors. Finally, levels of endogenous RAG1 and RAG2 were not down-regulated in TCRb-transgenic immature thymocytes undergoing allelic or isotypic exclusion. Collectively, our data reveal a critical but lineage-nonspecific role for pTa in mediating both allelic and isotypic exclusion in TCRb-transgenic mice. IntroductionT cells can be divided into ab and cd lineages based on their expression of TCRab or TCRcd. During development in the thymus, ab and cd lineages separate at an early CD4 -CD8 -double-negative (DN) stage, but the precise mechanism of lineage divergence remains controversial.One molecule that has been postulated to play a key role in ab/cd lineage commitment is the pTa chain. pTa is a critical component of the pre-TCR which consists, in addition, of a functionally rearranged TCRb chain and CD3 signaling components. Signaling through the pre-TCR has been reported to be responsible for many important functions during the development of ab lineage cells, including TCRb allelic exclusion [1-3], TCRc silencing [4], and extensive proliferation during the transition from DN to CD4 + CD8 + double-positive (DP) stages [5]. Since pTa -/-mice have an increased number of cd cells that harbor an increased frequency of in-frame TCRb rearrangements [6], it has also been proposed that the pre-TCR favors ab lineage commitment at the expense of cd cells [6]. Since functions of pTa are often difficult to study in normal mice, several groups have crossed pTa-deficient mice with TCRb-transgenic (Tg) mice to assess various putative roles for the pre-TCR during thymus development [7,8]. However, the results of these studies are in many cases controversial and it is still not known whether transgenic "artifacts" caused by overexpression or premature expression of the transgenic TCRb chain may obscure the contribution of pTa to the observed phenotypes.In order to re-evaluate this issue in a systematic manner, we have utilized three independent TCRb Tg mouse...

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Section: Discussionsupporting

confidence: 88%

Section: Tcrb Transgenes Mediate Pta-dependent Allelic Exclusion In Csupporting

confidence: 60%

A critical lineage‐nonspecific role for pTα in mediating allelic and isotypic exclusion in TCRβ‐transgenic mice

Ferrero¹,

Grosjean²,

Fiorini³

et al. 2007

Eur J Immunol

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“…It has recently been suggested that B220 ϩ CD19 Ϫ pre-TCR␣ gene (pT␣) ϩ progeny of CLPs, termed CLP-2s, may seed thymus (43,44). Cells with a CLP-2 phenotype can be identified in the thymic DN1 compartment of pT␣ reporter mice, but appear considerably less efficient than ETPs in their T lineage potential (44).…”

Section: Cells (42) An Examination Of Early Progenitors In Ikarosmentioning

confidence: 99%

Early T Lineage Progenitors: New Insights, but Old Questions Remain

Bhandoola

Sambandam

Allman

et al. 2003

The Journal of Immunology

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“…In addition to jejunum and thymus, pT␣ a mRNA was also detected in mononuclear cells of bone marrow and blood. In a mouse strain with human CD25 as a pT␣-controlled reporter gene, it was recently shown that the bone marrow harbors the CD19 Ϫ lymphoid precursor that expresses pT␣ mRNA (41). However, these cells were not committed for development into ␣␤ T cells and pT␣ was even expressed before onset of TCR gene rearrangement.…”

Section: Cd3mentioning

confidence: 99%

Extrathymic TCR Gene Rearrangement in Human Small Intestine: Identification of New Splice Forms of Recombination Activating Gene-1 mRNA with Selective Tissue Expression

Bas

Hammarström

2003

The Journal of Immunology

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Two new 5′-untranslated region (5′UTR) exons were identified in the human gene for the lymphocyte-specific endonuclease recombination activating gene-1 (RAG1) required for the somatic recombination yielding functional Ag receptors. These 5′UTR exons were used in three different splice forms by jejunal lymphocytes of the T cell lineage. RAG1 mRNA containing the previously described 5′UTR exon was not expressed in these cells. Conversely, one of the new 5′UTR exons was not expressed in thymus. The new RAG1 mRNA splice forms were all expressed in immature T cells (CD2+CD7+CD3−). This cell population also expressed high levels of mRNA for the pre-T α-chain. In situ hybridization demonstrated jejunal cells expressing the new splice forms of RAG1 mRNA, both intraepithelially and in lamina propria. Pre-T α-chain mRNA-expressing cells were detected at the same sites. These results strongly suggest ongoing TCR gene rearrangement in human small intestinal mucosa, yielding T cells specially adapted for this environment. This seems to be achieved by two parallel processes, extrathymic T cell development and peripheral Ag-driven TCR editing.

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Tracing lymphopoiesis with the aid of a pTα-controlled reporter gene

Cited by 83 publications

References 42 publications

A critical lineage‐nonspecific role for pTα in mediating allelic and isotypic exclusion in TCRβ‐transgenic mice

A critical lineage‐nonspecific role for pTα in mediating allelic and isotypic exclusion in TCRβ‐transgenic mice

Early T Lineage Progenitors: New Insights, but Old Questions Remain

Extrathymic TCR Gene Rearrangement in Human Small Intestine: Identification of New Splice Forms of Recombination Activating Gene-1 mRNA with Selective Tissue Expression

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