Expression of T-cell antigen receptor genes during fetal development in the thymus

Snodgrass, H. Ralph; Dembić, Zlatko; Steinmetz, Michael; Boehmer, Harald von

doi:10.1038/315232a0

Cited by 275 publications

(109 citation statements)

References 30 publications

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“…Moreover, Northern analysis of thymus RNA revealed only the expression of a 1.0-kb TCR-fl message from normal and irradiated RAG-2-/-mice (data not shown). The 1.0-kb message has been reported to correspond to a germline-sterile transcript or to an incomplete D-J rearrangement of the TCR-B loci, which appears early in T cell development and which may precede full V-D-J rearrangement (16)(17)(18).…”

Section: Resultsmentioning

confidence: 99%

Sublethal gamma-radiation induces differentiation of CD4-/CD8- into CD4+/CD8+ thymocytes without T cell receptor beta rearrangement in recombinase activation gene 2-/- mice.

Zúñiga‐Pflücker

Jiang

Schwartzberg

et al. 1994

The Journal of Experimental Medicine

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SummaryDNA recombination of the immunoglobulin (Ig) or T cell receptor (TCR) gene loci is an essential step in the production of lymphocytes bearing antigen-specific receptors. Mice that lack the ability to rearrange their Ig and TCR gene loci are devoid of mature B and T cells. Complete rearrangement and expression of the TCR-fl chain has been suggested to allow immature thymocytes to switch from the CD4-/CD8-to the CD4 +/CD8 + stage of thymic development. Thus, thymocytes from severe combined immune deficient (SCID) mice or mice deficient in recombinase activation genes (RAG), which do not undergo proper DNA rearrangement, are arrested at the early CD4-/CD8-stage of development. B cell precursors in SCID or RAG mice do not progress from the B220 +/slgM-/heat stable antigen (HSA) +/CD43 + to the B220 +/slgM-/HSA + / CD43-stage. In an attempt to reconstitute RAG-2-/-mice with bone marrow-or fetal liver-derived progenitor cells, we subjected these mice to sublethal doses of v-radiation. It is surprising that in the absence of donor cells, irradiated RAG-2-/-mice revealed a dramatic change in their lymphoid phenotype. 14 d after irradiation, the majority of thymocytes had advanced to the CD4 +/CD8 + stage of T cell development and a small number of bone marrow precursors had progressed to the CD43-, HSA hi stage of B cell development. Analysis of the resulting CD4 +/CD8 + thymocytes revealed no surface expression of the TCR/CD3 complex and no V-D-J rearrangement of the TCR-B gene locus. Our findings provide evidence for a novel pathway that allows the transition of thymocytes from the CD4-/CD8-to the CD4 +/CD8 + stage and that does not appear to require TCR-fl chain rearrangement.T he ability of B and T lymphocytes to rearrange their respective Ig and TCR gene loci creates the diversity required for adaptive immune responses to foreign antigens. SCID mice and RAG-deficient mice, which cannot undergo proper DNA rearrangement, display a profound absence of B and T lymphocytes, and a loss of acquired immune function (1-4). These mice show an arrest in B and T cell development corresponding to the stage before that of normal DNA rearrangement. The immature B (B220 +/slgM-/heat stable antigen [HSA] +/CD43 +) and T (CD4-/CDS-/IL-2R +) cells in such mice cannot further differentiate because of a lack of expression of properly rearranged Ig or TCR gene products (2, 4). In fact, this requirement has been validated in the T lineage by experiments that show that thymocytes either from TCR-o~ -/-mice or RAG-/-mice which carry a TCR-~/chain transgene can continue differentiating up to the CD4 +/CD8 + stage (5, 6). These findings suggest that successful TCR-B chain rearrangement and expression trigger a pathway for the expression of CD4 and CD8, which has been termed "B-selection" (7-9). It was postulated that cells which fail to produce a/5 chain, i.e., "unselected" immature T cells, are eliminated. In an effort to use RAG-2-/-mice as hosts for thymic reconstitution, we were surprised to discover a striking effect of sublethal...

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Section: Resultsmentioning

confidence: 99%

Sublethal gamma-radiation induces differentiation of CD4-/CD8- into CD4+/CD8+ thymocytes without T cell receptor beta rearrangement in recombinase activation gene 2-/- mice.

Zúñiga‐Pflücker

Jiang

Schwartzberg

et al. 1994

The Journal of Experimental Medicine

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“…In mice and also humans, the majority of T cells developing in the thymus express the § g TCR on their surface, and the antigen recognition structure of both the TCR § and TCR g chains is produced through the rearrangement of segments of these genes [1,2]. It has been shown that rearrangement of the TCR g gene precedes that of the TCR § genes [3,4]. Cells that have succeeded in in-frame rearrangement of the TCR g gene express the TCR g chain together with the pre-TCR § chain [5], and then proliferate extensively prior to TCR § gene rearrangement [6,7].…”

Section: Introductionmentioning

confidence: 99%

Extensive proliferation of T cell lineage‐restricted progenitors in the thymus: an essential process for clonal expression of diverse T cell receptor β chains

et al. 2003

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For clonal diversification of TCR, a large number of T cell progenitors are required in which highly diverse TCR g chains are accommodated individually. In the present study, we examined the proliferative potential of thymic progenitors that have been defined to be T cell lineage restricted. We show that the earliest fetal thymus (FT) cells from Rag2 -/-mice, when cultured individually in a thymic organ culture system, produced 150-1,800 CD25 + cells. Since differentiation and proliferation of Rag2 -/-thymocytes are arrested at the stage of TCR g chain gene rearrangement, the observed proliferation was considered to represent the proliferative potential of progenitors prior to the TCR g rearrangement. A comparable level of proliferation was revealed to occur by analyzing the D g -J g rearrangement profiles of T cells generated from single progenitors in the earliest population of FT from normal mice. The proliferative potential of progenitors declined along with the progression of developmental stages. Such an extensive proliferation of progenitors after the restriction to the T cell lineage may be an essential process ensuring the clonal diversification of TCR g chains.

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“…The most immature population of thymocytes is generally defined as double negative (DN) or pro-T cells, which reflects the fact that they still do not express the co-receptor genes CD4 and CD8 which cooperatively with TCR bind to conserved regions of MHC class II and MHC class I molecules, respectively 7,8 . The DN thymocytes migrate from the cortico-medullary junction towards the outer cortex 9 and during migration through the thymic tri-dimensional meshwork, DN cells are induced to start the process of somatic gene rearrangements 10 . Concomitantly with migration and maturation of DN population the changes in expression pattern of cell surface molecules (CD44 and CD25) take place on the basis of which the DN maturation process can be monitored.…”

Section: Early Events In T Cell Development and Positive Selectionmentioning

confidence: 99%

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

Nedjic

Aichinger

Emmerich

et al. 2008

Nature

448

422

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Expression of T-cell antigen receptor genes during fetal development in the thymus

Cited by 275 publications

References 30 publications

Sublethal gamma-radiation induces differentiation of CD4-/CD8- into CD4+/CD8+ thymocytes without T cell receptor beta rearrangement in recombinase activation gene 2-/- mice.

Sublethal gamma-radiation induces differentiation of CD4-/CD8- into CD4+/CD8+ thymocytes without T cell receptor beta rearrangement in recombinase activation gene 2-/- mice.

Extensive proliferation of T cell lineage‐restricted progenitors in the thymus: an essential process for clonal expression of diverse T cell receptor β chains

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

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