Cutting Edge: Recombinase-Activating Gene Expression and V(D)J Recombination in CD4+CD3low Mature T Lymphocytes

Lantelme, Erica; Palermo, Belinda; Granziero, Luisa; Mantovani, Stefania; Campanelli, Rita; Monafò, V.; Lanzavecchia, Antonio; Giachino, Claudia

doi:10.4049/jimmunol.164.7.3455

Cited by 42 publications

(39 citation statements)

References 31 publications

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“…This is in good agreement with the recent reports on RAG1 and 2 mRNA expression and TCR gene rearrangement in blood CD4 ϩ T cells (34,35,36), although these studies did not allow distinction between RNA splice forms.…”

Section: Cd3supporting

confidence: 92%

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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Section: Cd3supporting

confidence: 92%

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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“…The risks inherent in one recently described mechanism, TCR revision, appear particularly large because it requires extrathymic Ag receptor gene rearrangement. Despite this implied risk, evidence from both mice and humans indicates that rearrangement of TCR genes by peripheral T cells can occur (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Although TCR revision can tolerize T cells to the initiating Ag (3,4,7,8), the danger of generating autoreactive cells through this mechanism is especially acute in autoimmune-prone mice (10,13).…”

mentioning

confidence: 99%

Cutting Edge: TCR Revision Occurs in Germinal Centers

Cooper

Turk

Sun

et al. 2004

The Journal of Immunology

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Mouse CD4+Vβ5+ T cells recognize a peripherally expressed superantigen encoded by an endogenous retrovirus. Ag encounter tolerizes the mature CD4 T cell compartment, either by deletion of autoreactive cells or by TCR revision. This latter process is driven by TCRβ rearrangement through RAG activity and results in the rescue of cells expressing novel TCRs that no longer recognize the tolerogen. Consistent with the notion that revising T cells represent a distinct peripheral T cell population, we now show that these lymphocyte blasts express a hybrid effector/memory phenotype and are not undergoing cell division. A population of revising T cells is CD40+, expresses the germinal center (GC) marker CXCR5, and is Vβ5lowThy-1low. Histology reveals that, consistent with their surface Ag phenotype, T cells undergoing TCR revision are enriched in splenic GCs. These data demonstrate that TCR revision is a multistep tolerance pathway supported by the unique microenvironment provided by GCs.

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“…Although RAG1 and RAG2 protein expression was often codetected in sorted CD4 ϩ V␤8.2 Ϫ T cells, it happened that only RAG1 was readily detectable. The reason for this difference is unclear, but, interestingly, a similar phenomenon has been reported for human mature CD4 ϩ CD3-low T cells that display RAG reexpression and initiate secondary V(D)J rearrangements (32).…”

Section: Discussionmentioning

confidence: 58%

T cells from epicutaneously immunized mice are prone to T cell receptor revision

Bynoe

Viret²,

Flavell³

et al. 2005

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

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Epicutaneous immunization of T cell receptor (TCR) transgenic (Tg) mice whose CD4 ؉ T cells are specific for the Ac1-11 fragment of myelin basic protein (MBP) with Ac1-11 elicits T cells with dominant suppressor͞regulatory activity that confers protection against Ac1-11-induced experimental autoimmune encephalomyelitis. We now report that such disease-resistant MBP TCR Tg mice also harbor a sizeable fraction of peripheral CD4 ؉ T cells lacking surface expression of the Tg TCR ␤ chain and expressing diverse, endogenously rearranged TCR ␤ chains. Ex vivo incubation at physiological temperature caused the loss of neo-␤-chain expression and reversion to the MBP ␣␤ TCR ؉ phenotype. The presence of recombination activating gene 1 and 2 proteins in CD4 ؉ T cells with revised TCRs was consistent with effective V(D)J recombination activity. The emergence of these cells did not depend on the thymic compartment. We conclude that in mice epicutaneously immunized with an autoantigen, peripheral specific T cells are susceptible to multiple mechanisms of tolerance.

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Cutting Edge: Recombinase-Activating Gene Expression and V(D)J Recombination in CD4+CD3low Mature T Lymphocytes

Cited by 42 publications

References 31 publications

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

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

Cutting Edge: TCR Revision Occurs in Germinal Centers

T cells from epicutaneously immunized mice are prone to T cell receptor revision

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