Thymic emigrants isolated by a new method possess unique phenotypic and functional properties

Lee, Chong Kil; Kim, Kyungjae; Li, Renhao; Murphy, William J.; Muegge, Kathrin; Durum, Scott K.

doi:10.1182/blood.v97.5.1360

Cited by 35 publications

(42 citation statements)

References 31 publications

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“…4, E and F) thymocytes were also increased in TCS1P 1 KO mice relative to controls. High expression of these markers is characteristic of fully mature thymocytes with potential for thymic emigration (30,31). In particular, single positive CD4ϩCD8Ϫ and CD4ϪCD8ϩ cells from TCS1P 1 KO mice expressed higher levels of CD62L than controls (Fig.…”

Section: Tcs1p 1 Ko Mice Have Decreased Numbers Of T-cell Lymphocytesmentioning

confidence: 99%

Expression of the Sphingosine 1-Phosphate Receptor, S1P1, on T-cells Controls Thymic Emigration

Allende

Dreier

Mandala

et al. 2004

Journal of Biological Chemistry

411

381

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S1P 1 is a widely distributed G protein-coupled receptor whose ligand, sphingosine 1-phosphate, is present in high concentrations in the blood. The sphingosine 1-phosphate receptor-signaling pathway is believed to have potent effects on cell trafficking in the immune system. To determine the precise role of the S1P 1 receptor on T-cells, we established a T-cell-specific S1P 1 knock-out mouse. The mutant mice showed a block in the egress of mature T-cells into the periphery. The expression of the S1P 1 receptor was up-regulated in mature thymocytes, and its deletion altered the chemotactic responses of thymocytes to sphingosine 1-phosphate. The results indicated that the expression of the S1P 1 receptor on T-cells controls their exit from the thymus and entry into the blood and, thus, has a central role in regulating the numbers of peripheral T-cells.Sphingolipids are important signaling molecules in a variety of biologic contexts (1-3). Sphingosine 1-phosphate, in one paradigm, binds to members of a family of G protein-coupled receptors (S1P 1-15 ) triggering diverse effects including proliferation, survival, migration, morphogenesis, adhesion molecule expression, and cytoskeletal changes (4 -8).S1P 1 /Edg 1 , the first of these receptors described (9, 10), couples to a G i pathway. During embryonic development, the S1P 1 receptor is highly expressed in the vascular system. Gene disruption in mice has demonstrated an essential function of the S1P 1 receptor in endothelial cells for the formation of a stable vascular network (11,12).The S1P 1 receptor is widely expressed in the adult, in particular in endothelial cells, the brain, and the heart, and also in the cells of the immune system (13, 14). S1P 1 and S1P 4 receptors have been detected in T-lymphocytes (15-17). Stimulation of receptor signaling has been found to mediate and regulate cell migration and suppress proliferation and cytokine production (17, 18). Recently, S1P 1 receptors have also been implicated in lymphocyte trafficking and homing as the result of studies using FTY720, a potent immunosuppressive agent. FTY720, a sphingosine analogue, is phosphorylated by sphingosine kinase type I and more efficiently by sphingosine kinase type II (19 -21) and functions as an agonist ligand for S1P 1 , S1P 3 , S1P 4 , and S1P 5 receptors (19,22). FTY720 causes lymphopenia through sequestration of circulating lymphocytes within lymph nodes and Peyer's patches (19,(22)(23)(24) and also blocks the egress of T-cells from the thymus (25, 26). However, it is not known at which S1P receptor and cell type FTY720 exerts its effects.To begin to address the physiologic function of the S1P 1 receptor and sphingosine 1-phosphate signaling in T-cells, we have generated a T-cell-specific mouse knock-out of the S1P 1 receptor using the Cre/loxP system. Our results with these mice reveal a crucial role for the S1P 1 receptor in the egress of mature T-cells from the thymus into the circulation. EXPERIMENTAL PROCEDURESGeneration of the S1P 1 loxP/loxP Lck-Cre Mice-We previously g...

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Section: Tcs1p 1 Ko Mice Have Decreased Numbers Of T-cell Lymphocytesmentioning

confidence: 99%

Expression of the Sphingosine 1-Phosphate Receptor, S1P1, on T-cells Controls Thymic Emigration

Allende

Dreier

Mandala

et al. 2004

Journal of Biological Chemistry

411

381

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“…Phenotypically, RTE are distinct from most medullary thymocytes (8), yet as a group they also do not fully resemble peripheral naive T cells, as they collectively retain low levels of HSA and have not yet fully up-regulated Qa2 like their peripheral counterparts (8,16). Some RTE derived from neonatal mice may also express elevated levels of CTLA4 (17), which could suggest reduced functional capacity. In terms of function, an early study showed that the adult RTE proliferative and cytotoxic response to stimulation in vitro was similar to that of peripheral T cells (18).…”

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confidence: 99%

“…Another study, however, suggested that RTE, identified using a novel system involving the expression of GFP under the control of the RAG-2 promoter, were less able to up-regulate CD25 in response to stimulation and displayed an attenuated proliferative response (20). Similarly, RTE derived from fetal thymus organ culture were unable to elicit acute graftvs-host disease when transferred into allogeneic mice (17), although it is not clear whether the behavior of these in vitro RTE is equivalent to freshly isolated adult RTE. Collectively, these studies suggest that the thymic medullary sojourn sees positively selected thymocytes make the transition from being susceptible to deletion by TCR signaling, to acquiring the functional capacity to respond to TCR signals by undergoing activation, although this may not be fully complete until after they reach the periphery.…”

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confidence: 99%

Antigen Challenge Inhibits Thymic Emigration

Uldrich

Berzins

Malin

et al. 2006

The Journal of Immunology

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T cell development in the thymus involves a series of TCR-mediated control points including TCR-β selection and positive and negative selection. Approximately half of the thymic sojourn is spent in the medulla, where thymocytes undergo final maturation before emigrating to the periphery. Although it is acknowledged that thymic emigration is an active process, relatively little is known about how this is regulated, why it takes so long, and whether TCR-mediated signaling can influence this step. Using wild-type and TCR transgenic mice, we found that Ag injected i.v. or intrathymically led to a striking reduction in the number of recent thymic emigrants (RTE) in the periphery. This was caused by inhibition of T cell export rather than peripheral deletion, because a cohort of RTE that was already released before in vivo Ag challenge was not depleted, and similar results were observed in Bim-deficient mice, which have impaired T cell deletion. Within the thymus, the loss of RTE was associated with retention of medullary thymocytes rather than increased negative selection. In addition to Ag-specific inhibition of export, some TCR-independent suppression of emigration was also observed that appeared to be partly the result of the inflammatory cytokine TNF. Thus, in addition to its accepted role in intrathymic selection events, TCR signaling can also play an important role in the regulation of thymic emigration.

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“…Characterization of RTE has been controversial. Up-regulation of several markers on SP CD8 thymocytes undergoing positive selection and emigration, including CD5 (39), ␤ 7 integrin, CD44 and L-selectin (CD62L) has been reported (33,40), whereas others did not observe these changes (41). Our data further demonstrate the heterogeneity of the phenotypes of SP CD8 thymocyte subpopulations affected by positively selecting ligands, as well as difficulties in the precise characterization of the small subpopulation of RTE.…”

Section: Discussionmentioning

confidence: 68%

Peptide Variants of Viral CTL Epitopes Mediate Positive Selection and Emigration of Ag-Specific Thymocytes In Vivo

Fridkis-Hareli

Reche²,

Reinherz³

2004

The Journal of Immunology

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During development, thymocytes carrying TCRs mediating low-affinity interactions with MHC-bound self-peptides are positively selected for export into the mature peripheral T lymphocyte pool. Thus, exogenous administration of certain altered peptide ligands (APL) with reduced TCR affinity relative to cognate Ags may provide a tool to elicit maturation of desired TCR specificities. To test this “thymic vaccination” concept, we designed APL of the viral CTL epitopes gp33–41 and vesicular stomatitis virus nucleoprotein octapeptide N52–59 relevant for the lymphocytic choriomeningitis virus-specific P14- and vesicular stomatitis virus-specific N15-TCRs, respectively, and examined their effects on thymocytes in vivo using irradiation chimeras. Injection of APL into irradiated congenic (Ly-5.1) mice, reconstituted with T cell progenitors from the bone marrow of P14 RAG2−/− (Ly-5.2) or N15 RAG2−/− (Ly-5.2) transgenic mice, resulted in positive selection of T cells expressing the relevant specificity. Moreover, the variants led to export of virus-specific T cells to lymph nodes, but without inducing T cell proliferation. These findings show that the mature T cell repertoire can be altered by in vivo peptide administration through manipulation of thymic selection.

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Thymic emigrants isolated by a new method possess unique phenotypic and functional properties

Cited by 35 publications

References 31 publications

Expression of the Sphingosine 1-Phosphate Receptor, S1P1, on T-cells Controls Thymic Emigration

Expression of the Sphingosine 1-Phosphate Receptor, S1P1, on T-cells Controls Thymic Emigration

Antigen Challenge Inhibits Thymic Emigration

Peptide Variants of Viral CTL Epitopes Mediate Positive Selection and Emigration of Ag-Specific Thymocytes In Vivo

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