The thymic microenvironment

Boyd, Richard; Tucek, C L; Godfrey, Dale I.; Izon, David J.; Wilson, Trevor; Davidson, Natalie J.; Bean, Andrew G.D.; Ladyman, Heather M.; Ritter, Mary A.; Hugo, Patrice

doi:10.1016/0167-5699(93)90248-j

Cited by 430 publications

(270 citation statements)

References 318 publications

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“…6A), with some Ehox remaining in the ventral end of the second pouch. The third pharyngeal pouch forms the early thymic primordium, which from day 11 onward, becomes populated by lymphoid progenitor cells (Boyd et al, 1993). Quantitative RT-PCR analysis reveals expression of Ehox is approximately 10-fold higher in the thymus of a newborn animal compared with 1-, 2-, and 22-month-old thymii (Fig.…”

Section: Figmentioning

confidence: 98%

Expression of a novel homeobox gene Ehox in trophoblast stem cells and pharyngeal pouch endoderm

Jackson

Baird

Nichols

et al. 2003

Developmental Dynamics

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Ehox is an X-linked paired like homeobox gene identified from a differentiating embryonic stem (ES) cell cDNA library and is expressed at low levels in the preimplantation blastocyst and in ES cells in vitro. In embryos at 6.5 days post coitum (dpc), Ehox expression was restricted to the extraembryonic ectoderm which correlates with high-level expression in cultures of trophoblast stem cells. Extraembryonic expression becomes further restricted to the chorion and by 15.5 dpc Ehox is expressed in chorionic trophoblast of the labyrinth and spongiotrophoblast layers of the placenta. Ehox expression in the embryo proper first appears at 8.5 dpc in the anterior foregut endoderm and by 9.5 dpc is visible in pharyngeal pouches 2-4. By 10.5 dpc, Ehox expression becomes restricted to the ventral end of pouches 2 and 3. The data presented here is the first description of Ehox expression during embryogenesis and suggests a dual role for Ehox: (1) in trophoblast stem cells and compartments of the developing placenta, and (2) during development of the pharyngeal pouches, possibly delineating the area to become thymus. Developmental Dynamics 228:740 -744, 2003.

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Section: Figmentioning

confidence: 98%

Expression of a novel homeobox gene Ehox in trophoblast stem cells and pharyngeal pouch endoderm

Jackson

Baird

Nichols

et al. 2003

Developmental Dynamics

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“…Thymocyte modification during positive selection establishes a mechanism for preventing peripheral autoimmunity. Previous experiments have shown that thymic epithelium is capable of mediating positive (56) and negative selection (57)(58)(59)(60). Therefore, it is possible that positive selection and thymocyte modification leading to unresponsiveness both occur during interactions with the thymic epithelium.…”

mentioning

confidence: 99%

Mature T cell reactivity altered by peptide agonist that induces positive selection.

Sebzda

Kündig

Thomson

et al. 1996

The Journal of Experimental Medicine

144

100

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SummaryRecent studies have investigated how defined peptides influence T cell development. Using a T cell receptor-transgenic [32-microglobulin--deficient model, we have examined T cell maturation in fetal thymic organ cultures in the presence of various peptides containing single-alanine substitutions of the strong peptide agonist, p33. Cocultivation with the peptide A4Y, which contains an altered T cell contact residue, resulted in efficient positive selection. Several in vitro assays demonstrated that A4Y was a moderate agonist relative to p33. Although A4Y promoted positive selection over a wide concentration range, high doses of this peptide could not induce clonal deletion. Thymocytes maturing in the presence of A4Y were no longer able to respond to A4Y, but could proliferate against p33. These studies demonstrate that (a) peptides that induce eflficient positive selection at high concentrations are not exclusively antagonists; (b) some agonists do not promote clonal deletion; (c) positive selection requires a unique T cell receptor-peptide-major histocompatibility complex interaction; and (d) interactions with selecting peptides during T cell ontogeny may define the functional reactivity of mature T cells. T CRs expressed on maturing thymocytes interact withpeptide-MHC complexes on thymic stromal cells and transmit signals that lead to either positive or negative T cell selection (1-3). Positive selection is an active process that rescues self-MHC-restricted thymocytes from programmed cell death. In contrast, negative selection tolerizes potentially autoreactive T cells, either through clonal deletion or unresponsiveness. Clonal deletion physically removes thymocytes by inducing apoptosis, as compared with unresponsiveness, which modifies developing T cells so that they can no longer respond against the tolerizing antigen. Since positive and negative selection shape the TCR repertoire and define the basis of self-/non-self-antigens, much research has focused on understanding T cell development. Studies have addressed how clonotypic TCRs expressed on CD4+CD8 + double-positive thymocytes can distinguish between these two selection events. Although it has been demonstrated that peptides are involved in positive and negative selection (4, 5), it remains controversial whether the selecting ligand has a qualitative or quantitative role in determining the fate of the developing T cell.Recently, altered peptide ligands have been identified that can inhibit some or all mature T cell effector functions (6-10). Antagonist peptides are defined as ligands that engage TCRs and actively inhibit biological responses. Partial agonists are closely related peptides that stimulate a subset ofT cell effector functions (11). This is in contrast with agonist peptides, which induce a complete range ofT cell responses. Studies by Hogquist et al. (12,13) and Jameson et al. (14) showed a correlation between peptide antagonists and positive selection. These results suggest that a positively selecting peptide is qualitatively diffe...

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“…Only a minority (ϳ3%) of the DP cells are positively selected to generate mature single positive (SP) helper (CD4 ϩ CD8 Ϫ ) and cytotoxic (CD4 Ϫ CD8 ϩ ) T cells (9). The developmental progression from immature to mature thymocytes occurs sequentially and in distinct thymic microenvironments (10).…”

mentioning

confidence: 99%

Normal Thymic Architecture and Negative Selection Are Associated with Aire Expression, the Gene Defective in the Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)

Žuklys

Balc̆iūnaite

Agarwal

et al. 2000

The Journal of Immunology

234

159

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T cell development is tightly controlled by thymic stromal cells. Alterations in stromal architecture affect T cell maturation and the development of self-tolerance. The monogenic autoimmune syndrome APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy) is characterized by the loss of self-tolerance to multiple organs. Although mutations in the autoimmune regulator (AIRE) gene are responsible for this disease, the function of AIRE is not known. Here we report on the spatial and temporal pattern of murine Aire expression during thymic ontogeny and T cell selection. Early during development, thymic Aire transcription is critically dependent on RelB and occurs in epithelial cells in response to lymphocyte-mediated signals. In adult tissue, Aire expression is confined to the medulla and the corticomedullary junction, where it is modulated by thymocytes undergoing negative selection. Aire may determine thymic stromal organization and with it the induction of self-tolerance.

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The thymic microenvironment

Cited by 430 publications

References 318 publications

Expression of a novel homeobox gene Ehox in trophoblast stem cells and pharyngeal pouch endoderm

Expression of a novel homeobox gene Ehox in trophoblast stem cells and pharyngeal pouch endoderm

Mature T cell reactivity altered by peptide agonist that induces positive selection.

Normal Thymic Architecture and Negative Selection Are Associated with Aire Expression, the Gene Defective in the Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)

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