Discrimination between thymic epithelial cells and peripheral antigen-presenting cells in the induction of immature T cell differentiation

Poirier, Ghislaine; Lo, David; Reilly, Christina R.; Kaye, Jonathan

doi:10.1016/1074-7613(94)90069-8

Cited by 16 publications

(5 citation statements)

References 35 publications

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“…The DPK cell line was derived from a CD4 ϩ 8 ϩ thymic lymphoma of an AND TCR transgenic mouse (38,45). This cell line possess the phenotype of immature thymocytes, including expression of RAG-1,2 and TdT (41), and can be triggered to differentiate into CD4 ϩ 8 Ϫ cells upon activation by a pigeon cytochrome c peptide and E k bearing antigen-presenting cells, or alternatively, by E k bearing thymic epithelial cells in vivo or in vitro in the ab-sence of antigen (38,46). Although anti-CD3 mAb alone is a relatively poor inducer of DPK cell differentiation, it is active at high concentration or in conjunction with accessory molecule stimulation (41,47).…”

Section: Resultsmentioning

confidence: 99%

Induction of the Early Growth Response (Egr) Family of Transcription Factors during Thymic Selection

Shao

Kono

Chen

et al. 1997

The Journal of Experimental Medicine

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131

116

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There is little known about the regulation of gene expression during TCR-mediated differentiation of immature CD4+8+ (double positive) thymocytes into mature T cells. Using the DPK CD4+8+thymocyte precursor cell line, we demonstrate that the early growth response-1 gene (Erg-1), encoding a zinc finger transcription factor, is rapidly upregulated after TCR stimulation. We also report that Egr-1 is expressed by a subset of normal double positive thymocytes in the thymic cortex, as well by a majority of medullary single positive thymocytes. Expression of Egr-1 is dramatically reduced in the thymus of major histocompatibility complex knockout mice, but can be induced by anti-CD3 antibody stimulation of isolated thymocytes from these animals. These and other data suggest that high level expression of Egr-1 in the thymus is a consequence of selection. A similar pattern of expression is found for family members Egr-2 and Egr-3. Using the DPK cell line, we also demonstrate that expression of Egr-1, 2, and 3 is dependent upon ras activation, as is the initiation of differentiation to a single positive cell. In contrast, the calcineurin inhibitor cyclosporin A, which inhibits DPK cell differentiation as well as positive selection, inhibits expression of Egr-2 and Egr-3, but not Egr-1. The identification of the Egr family in this context represents the first report of a link between the two known signaling pathways involved in positive selection and downstream transcriptional regulators.

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Section: Resultsmentioning

confidence: 99%

Induction of the Early Growth Response (Egr) Family of Transcription Factors during Thymic Selection

Shao

Kono

Chen

et al. 1997

The Journal of Experimental Medicine

Self Cite

131

116

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show abstract

“…That T cell receptor-dependent interaction of DPK cells with thymic epithelial MHC II proteins in vivo and in vitro without PCC antigen initiates conversion to CD4 / 8 0 T cells, whereas non-thymic antigen-presenting cells require PCC for the same activity, suggested the possibility of dependence on other factors in the thymic milieu (31). T cell receptors were found concurrently to mediate up-regulation of selected surface receptors and intracellular proteins critical for thymocyte survival and differentiation (32).…”

Section: Discussionmentioning

confidence: 99%

Vasoactive intestinal peptide enhancement of antigen-induced differentiation of a cultured line of mouse thymocytes

et al. 1998

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The prominence of vasoactive intestinal peptide (VIP) in rodent thymic neurons suggested that this potent mediator of T cell functions may alter developmental responses of thymocytes to T cell receptor (TCR) -dependent stimulation. CD4+8+ DPK cells derived from a thymic lymphoma of a TCR transgenic mouse respond to pigeon cytochrome C (PCC) antigen in association with distinct I-E MHC II haplotypes on antigen-presenting cells (APCs) by differentiating into CD4+8- T cells. The specific recognition of VIP by two types of homologous G-protein-coupled receptors (VIPR1 and VIPR2) on DPK cells was attributable predominantly to VIPR1 before and to VIPR2 after exposure to APCs and PCC, as assessed by quantification of the respective mRNAs. PCC-evoked differentiation of DPK cells was enhanced significantly by 1 to 100 nM VIP after 3 to 4 days. The effects of VIP analogs with VIPR type selectivity implied that VIP enhancement of differentiation of DPK cells was mediated principally by VIPR2. Differential reduction in the expression of each type of VIPR by transfection of DPK cells with plasmids encoding the respective antisense mRNAs confirmed the central role of VIPR2 in VIP-enhanced conversion to CD4+8- T cells. The suppression of DPK cell differentiation by inhibitors of adenylyl cyclase and protein kinase A suggested a transductional role for VIP-elicited increases in [cAMP]i. That the changes in frequency of CD4+8+ and CD4+8- DPK cells reflected principally differentiation was supported by the lack of consistent differences between the two subsets in the effects of VIP and VIPR2 agonist on cell number, viability, apoptosis, and proliferation. VIP may be one endogenous mediator that explains the unique thymic microenvironment for topographically specific development of T cells.

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“…DP thymocyte cell line, DPK cells 59 were obtained from J. G. Kaye (The Scripps Research Institute, La Jolla, CA, USA) and maintained in RPMI1640 medium (SIGMA) supplemented with 10% fetal bovine serum (FBS) (SIGMA), 100 U ml −1 penicillin, 10 μg ml −1 streptomycin, 50 μM 2-mercaptoehthanol, 0.1 mM non-essential amino acids and 1 mM sodium pyruvate. Murine fibroblast cell line DCEK transfected with I–E k was kindly provided by K. Yasutomo (Tokushima University, Tokushima, Japan) and maintained in DMEM medium (SIGMA) supplemented with 10% FBS, 100 U ml −1 penicillin, 10 μg ml −1 streptomycin and 50 μM 2-mercaptoehthanol.…”

Section: Methodsmentioning

confidence: 99%

Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1

et al. 2016

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Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. Here, we show that a serine/threonine kinase, protein kinase D (PKD), is crucial for thymocyte positive selection. In T cell-specific PKD-deficient (PKD2/PKD3 double-deficient) mice, the generation of CD4 single positive thymocytes is abrogated. This defect is likely caused by attenuated TCR signalling during positive selection and incomplete CD4 lineage specification in PKD-deficient thymocytes; however, TCR-proximal tyrosine phosphorylation is not affected. PKD is activated in CD4+CD8+ double positive (DP) thymocytes on stimulation with positively selecting peptides. By phosphoproteomic analysis, we identify SH2-containing protein tyrosine phosphatase-1 (SHP-1) as a direct substrate of PKD. Substitution of wild-type SHP-1 by phosphorylation-defective mutant (SHP-1S557A) impairs generation of CD4+ thymocytes. These results suggest that the PKD–SHP-1 axis positively regulates TCR signalling to promote CD4+ T cell development.

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Discrimination between thymic epithelial cells and peripheral antigen-presenting cells in the induction of immature T cell differentiation

Cited by 16 publications

References 35 publications

Induction of the Early Growth Response (Egr) Family of Transcription Factors during Thymic Selection

Induction of the Early Growth Response (Egr) Family of Transcription Factors during Thymic Selection

Vasoactive intestinal peptide enhancement of antigen-induced differentiation of a cultured line of mouse thymocytes

Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1

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