Differentiation and cell division in the mammalian thymus

Rothenberg, Ellen V.; Lugo, James P.

doi:10.1016/0012-1606(85)90114-9

Cited by 77 publications

(30 citation statements)

References 91 publications

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“…This finding is relevant both to the long-standing controversy over the precise pathway of thymocyte development and to various hypotheses concerning the role of interaction with MHC products in T-cell development. There is much evidence that most cells generated in the thymic cortex die there without maturing (6 death of the bulk of cortical thymocytes is attributed to the eventual elimination of self-tolerance of cells whose receptors fail to make the transition from recognition of MHC alone to recognition of antigen plus MHC (see below). Our data presented here and previously (7,8) support a third point of view between these two extremes.…”

Section: Rationale the Anti-receptor Antibody Kj16-133 (Kj16)mentioning

confidence: 99%

The role of the T-cell receptor in thymocyte maturation: effects in vivo of anti-receptor antibody.

McDuffie¹,

Born²,

Marrack³

et al. 1986

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

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The T-cell receptor, which recognizes antigen plus a product of the major histocompatibility complex, has been postulated to drive T-cell maturation in the thymus by engaging major histocompatibility complex proteins expressed on thymic stromal cells. We tested this idea by injecting neonatal animals with an anti-receptor antibody, KJ16, that binds to about 20% of T cells and is capable of blocking receptor function. In the presence of this antibody, mature T cells bearing the KJ16 epitope failed to develop. On the other hand, although the antibody could be shown to bind to receptors on cortical thymocytes, it did not prevent the rapid expansion or survival of the bulk of the KJ16+ cells in this population. These results are consistent with the hypothesis that most cortical thymocytes arise by a receptor-independent mechanism and that only a small proportion of these cells mature by a process dependent on receptor-major histocompatibility complex interactions. With the discovery of the T-cell receptor for antigen, several laboratories have examined thymocytes both for the expression of the immunoglobulin-like genes that encode the a and f3 chains of the receptor and for the appearance of the receptor protein in an attempt to shed some light on the question of MHC restriction (7-11). Data support the view that stem cells enter the thymus with both the a and P3 chain genes in germ-line configuration. They rearrange and express sequentially first the /3-chain genes, then the a-chain genes. In the present study we have attempted to block the function of T-cell receptors in the thymus with an antireceptor antibody to test directly the hypothesis that engagement of the receptor by MHC products plays a crucial role in T-cell maturation. This antibody, administered to newborn mice, had no apparent effect on the bulk of receptor-bearing cortical thymocytes, but prevented the appearance of mature KJ16+ medullary thymocytes or peripheral T cells. These results demonstrate the importance of the receptor in thymocyte maturation but suggest that only a small proportion of cortical thymocytes is involved in receptor-mediated selection.

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Section: Rationale the Anti-receptor Antibody Kj16-133 (Kj16)mentioning

confidence: 99%

The role of the T-cell receptor in thymocyte maturation: effects in vivo of anti-receptor antibody.

McDuffie¹,

Born²,

Marrack³

et al. 1986

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

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“…Several encode proteins which are required for the thymocytes to mature into T cells capable of functioning in the immune system, for example, (i) the T-cell receptor for antigen (TCR) and the associated CD3 proteins which are required for antigen recognition and signaling; (ii) CD24 (the interleukin-2 [IL-2] receptor) which must be expressed for the cells to respond to the cytokine IL-2; (iii) gene products important for signal transduction after antigen recognition, such as CD3, CD4, CD8, and CD45; (iv) gene products involved in T-cell homing to peripheral target organs; and (v) genes of unknown function involved in T-cell activation (7,14,20,33,44). There is remarkable heterogeneity in thymocyte subsets which express different combinations of expressed genes (reviewed in references 1, 14, and 44).…”

mentioning

confidence: 99%

Activated T cells express a novel gene on chromosome 8 that is closely related to the murine ecotropic retroviral receptor.

MacLeod¹,

Finley²,

Kakuda³

et al. 1990

Mol. Cell. Biol.

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A novel cDNA clone (20.5) which is differentially expressed between two closely related T-lymphoma cell clones was isolated by subtraction-enriched differential screening. SL12.4 cells, from which the cDNA was isolated, have characteristics of thymocytes at an intermediate stage in development. A sister cell clone derived from the same tumor, SL12.3, does not express this mRNA, has a distinct phenotype, and expresses fewer genes required for mature T-cell function. The cDNA sequence predicts a highly hydrophobic protein (approximately 49.5 kilodaltons) which contains seven putative membrane spanning domains. The gene was expressed on concanavalin A-activated T lymphocytes and was designated Tea (T-cell early activation gene). The Tea gene mapped to chromosome 8 and appeared to be conserved among mammalian and avian species. The Tea gene is distinct from, but bears extensive amino acid and DNA sequence similarity with, the murine ecotropic retroviral receptor which is encoded by the Rec-1 gene. Neither gene product displayed significant homology with other known transmembrane-spanning proteins. Thus, the Tea and Rec-1 genes establish a new family encoding multiple membrane-spanning proteins.

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“…Cell proliferation is an essential event in T-cell differentiation (7,8), and it is clear that cell activation is the first in a cascade of events driving thymocyte precursors (CD4-CD8-) to cortical thymocytes (CD4+ CD8+) and to mature medullary cells (single positive, essentially CD4+ CD8-) (9-12). Treatment of mice by specific cell-proliferation inhibitors leads to transient cessation of cell generation and of differentation.…”

Section: Introductionmentioning

confidence: 99%

“…In the fetus (3-5) as well as in the adult (6), all thymocytes develop from exogenously produced precursors that colonize the organ. In the adult steady-state thymus, the study of the properties of recently immigrated precursors and of the early events leading to differentiation is rendered difficult by the asynchronous coexistence of successive steps and by the fact that these precursors represent a very minor subset.Cell proliferation is an essential event in T-cell differentiation (7,8), and it is clear that cell activation is the first in a cascade of events driving thymocyte precursors (CD4-CD8-) to cortical thymocytes (CD4+ CD8+) and to mature medullary cells (single positive, essentially CD4+ CD8-) (9-12). Treatment of mice by specific cell-proliferation inhibitors leads to transient cessation of cell generation and of differentation.…”

mentioning

confidence: 99%

Cell proliferation and thymocyte subset reconstitution in sublethally irradiated mice: compared kinetics of endogenous and intrathymically transferred progenitors.

Pénit

Ezine

1989

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

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After sublethal (6 Gy) whole-body irradiation, the C57BL/Ba (Thy-1.1) murine thymus regenerated in two waves, on days 3-10 and 25-32, separated by a severe relapse. The second phase of depletion-reconstitution reproduced the first one, in a less synchronous manner. The depletion affected all cell subsets, but CD4+ CD8-cells decreased later than immature cells. Cell proliferation, measured by BrdUrd incorporation, started on day 3 after irradiation and concerned CD4-CD8-, CD4-CD8+, and CD4+ CD8+ cells, sequentially. CD4+ CD8-cells never represented a significant percentage of cycling cells. When irradiation was immediately followed by an intrathymic inJection of 105 C57BL/Ka (Thy-1.2) bone marrow cells, the relapse in thymus reconstitution was no longer observed. Detected with anti-Thy-1.2 antibodies, donor cells started cycling on day 14 and showed only one wave of proliferation. In these chimeras, recipient thymocytes behave exactly like thymocytes ofsolely irradiated mice. Intrathymically transferred CD4-CD8-thymocytes (105) showed the same proliferation kinetics as endogenous cells, with a peak in number on day 10 but completely disappeared from the thymus on days 14-21. These data reflect maturational differences between intrathymic and bone marrow precursor cells and suggest different radiosensitivities not linked to proliferative status. The resting state of the thymus immigrants was shown by the absence of Thy-i acquisition by bone marrow cells continuously labeled for 10 days with BrdUrd in vivo before intrathymic transfer. When such labeled bone marrow cells were injected in the thymus, only the minor BrdUrd-subset gave rise to Thy-1+ cells.All thymocyte subsets represent intermediary stages of the T-cell differentiation pathway, which can be followed in particular by CD4 and CD8 surface expression (1,2). In the fetus (3-5) as well as in the adult (6), all thymocytes develop from exogenously produced precursors that colonize the organ. In the adult steady-state thymus, the study of the properties of recently immigrated precursors and of the early events leading to differentiation is rendered difficult by the asynchronous coexistence of successive steps and by the fact that these precursors represent a very minor subset.Cell proliferation is an essential event in T-cell differentiation (7,8), and it is clear that cell activation is the first in a cascade of events driving thymocyte precursors (CD4-CD8-) to cortical thymocytes (CD4+ CD8+) and to mature medullary cells (single positive, essentially CD4+ CD8-) (9-12). Treatment of mice by specific cell-proliferation inhibitors leads to transient cessation of cell generation and of differentation. Thymus regeneration then takes place by a synchronous development of progenitors. By combining DNA synthetic labeling and cell-surface phenotype analysis, we have been able to elucidate the early events leading to sequential differentiation of thymocyte subsets (11).Irradiation has been used widely to deplete the thymus; although its effects are not restric...

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Differentiation and cell division in the mammalian thymus

Cited by 77 publications

References 91 publications

The role of the T-cell receptor in thymocyte maturation: effects in vivo of anti-receptor antibody.

The role of the T-cell receptor in thymocyte maturation: effects in vivo of anti-receptor antibody.

Activated T cells express a novel gene on chromosome 8 that is closely related to the murine ecotropic retroviral receptor.

Cell proliferation and thymocyte subset reconstitution in sublethally irradiated mice: compared kinetics of endogenous and intrathymically transferred progenitors.

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