Early precursor thymocytes can produce interleukin 2 upon stimulation with calcium ionophore and phorbol ester.

Lugo, James P.; Krishnan, Santosh N.; Sailor, Rochelle D.; Rothenberg, Ellen V.

doi:10.1073/pnas.83.6.1862

Cited by 43 publications

(22 citation statements)

References 36 publications

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“…Indeed, DN thymocytes from the adult thymus are able to produce IL-2 and other cytokines in response to a TcR-independent stimulation (36,68). However, as thymocytes reach the DP stage, they can no longer produce cytokines upon stimulation (9,11,48).…”

Section: Discussionmentioning

confidence: 99%

“…Although resting triple-negative thymocytes from adult mice do not express any cytokines, expression can be induced by TcR-independent stimulation with phorbol esters and calcium ionophore (68). However, as these cells approach the DP stage, there is a striking loss in the ability to produce cytokines (11,36,48). In contrast, mature singlepositive thymocytes regain the capacity to express specific cytokines.…”

Section: Cd8mentioning

confidence: 99%

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Regulation of AP-1 and NFAT Transcription Factors during Thymic Selection of T Cells

Rincón

Flavell

1996

Molecular and Cellular Biology

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The ability of thymocytes to express cytokine genes changes during the different stages of thymic development. Although CD4 ؊ CD8 ؊ thymocytes are able to produce a wide spectrum of cytokines in response to a T-cell receptor (TcR)-independent stimulus, as they approach the double-positive (DP) CD4 ؉ CD8 ؉ stage, they lose the ability to produce cytokine. After the DP stage, thymocytes become single-positive CD4 ؉ or CD8 ؉ thymocytes which reacquire the ability to secrete cytokines. In an attempt to understand the molecular basis of this specific regulation, we use AP-1-luciferase and newly generated NFAT-luciferase transgenic mice to analyze the transcriptional and DNA-binding activities of these two transcription factors that are involved in the regulation of cytokine gene expression. Here, we show that both AP-1 and NFAT transcriptional activities are not inducible in the majority of DP cells but that during the differentiation of DP cells to the mature single-positive stage, thymocytes regain this inducibility. Subpopulation analysis demonstrates that this inducibility is reacquired at the DP stage before the down-modulation of one of the coreceptors. Indeed, AP-1 inducibility, just like the ability to express the interleukin-2 gene, is reacquired during the differentiation of DP TcR low CD69 low heat-stable antigen (HSA) high thymocytes to DP TcR high CD69 high HSA high cells, which is considered to be the consequence of the first signal that initiates positive selection. We therefore propose that the inability of DP thymocytes to induce AP-1 and NFAT activities is one of the causes for the lack of cytokine gene expression at this stage and that this inducibility is reacquired at the latest stage of DP differentiation as a consequence of positive selection. This could be a mechanism to prevent the activation of DP thymocytes before selection has taken place. (3,32,33,45,55,57,62) as well as MHC class II-and class I-deficient mice (10, 16) has shown that this decision is mediated by positive selection that is dictated by the interaction of a specific TcR, associated with a CD4 or CD8 coreceptor, with the appropriate positive-selecting MHC class II or class I, respectively, on epithelial cells of the thymus.Two models of thymocyte selection have been proposed to explain the decision of a DP cell to commit to the CD4 or CD8 lineage (6,50,66), although this question is still open. The instructive model proposes that positive selection occurs at the DP stage of maturation. A CD4 ϩ CD8 ϩ cell specifically interacts with MHC class I or class II molecules through its TcR and CD8 or CD4 coreceptor, respectively. The TcR-mediated signal may differ depending on which coreceptor binds to the MHC molecule, and it dictates whether thymocytes downmodulate CD8 or CD4 to proceed with differentiation. In contrast, the stochastic/selective model originally postulated that positive selection occurs at the single-positive stage of maturation. CD4 ϩ CD8 ϩ cells randomly shut off either CD4 or CD8 independently of the specificity...

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Section: Discussionmentioning

confidence: 99%

Section: Cd8mentioning

confidence: 99%

Regulation of AP-1 and NFAT Transcription Factors during Thymic Selection of T Cells

Rincón

Flavell

1996

Molecular and Cellular Biology

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“…However, to establish a physiological role for IL-4 in thymic development, it is also important to demonstrate its production by immature thymocytes. Previous studies have documented that immature thymocytes (adult double negative or fetal day 15) are able to produce IL-2 when induced with calcium ionophores (ionomycin or A23187) and PMA (3,4). These stimuli are actually mitogenic for these thymocytes, although their mechanism of action is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Workers in several laboratories have investigated the role of interleukin 2 (IL-2), a known growth factor for mature T cells, in early thymic development. Recent evidence indicates that IL-2 can be produced by thymocytes after appropriate stimulation (3,4). However, the potential role of IL-2 in T-cell ontogeny remains controversial, and several reports have concluded that IL-2, by itself, is unlikely to be responsible for the high proliferative rate of thymocytes (2,5).…”

mentioning

confidence: 99%

Interleukin 4 is a growth factor for activated thymocytes: possible role in T-cell ontogeny.

Zlotnik¹,

Ransom²,

Frank³

et al. 1987

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

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We have shown that recombinant or natural interleukin 4 (IL-4) (formerly called B-cell stimulatory factor 1) induces proliferation of activated adult or fetal thymocytes. In the case of adult thymocytes, IL-4 in combination with Con A or phorbol 12-myristate 13-acetate (PMA) stimulated the proliferation of peanut agglutinin (PNA)-negative (-) thymocytes, while PNA-positive (+) thymocytes showed only marginal responses. Further investigation revealed that day 14-17 fetal thymocytes, purified L3T4-LyT2-double-negative adult thymocytes, and single positive L3T4+ LyT2-or L3T4-LyT2+ thymocytes failed to respond to IL-4 or PMA alone but proliferated strongly with both IL-4 and PMA. In contrast, purified double-positive L3T4+ LyT2+ adult thymocytes showed only a marginal proliferative response to these stimuli. Responsiveness of thymic subpopulations to PMA and IL-4 could be inhibited with anti-IL-4 but not with anti-IL-2 monoclonal antibodies, indicating that they were IL-2 independent. Finally, we have observed that supernatants from calcium ionophore and PMA-stimulated adult double-negative L3T4-LyT2-thymocytes induce proliferation of doublenegative adult thymocytes. This latter response is inhibited by anti-IL-4 monoclonal antibodies, suggesting that under appropriate stimulation conditions, these immature thymocytes are able to produce IL-4. These observations suggest a role for IL-4 in T-cell ontogeny.

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“…that go on to full maturation (9,17,24,38,39). Neither the early inducibility nor the extinction of inducibility is well understood in relation to the generation of mature IL-2 producers.…”

mentioning

confidence: 99%

Molecular basis for developmental changes in interleukin-2 gene inducibility.

Chen

Rothenberg

1993

Mol. Cell. Biol.

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At least three stages in the intrathymic development of pre-T cells are demarcated by differences in the competence to express the interleukin-2 (IL-2) gene as an acute response to stimulation. IL-2 inducibility appears to be acquired relatively early, prior to T-cell receptor (TcR) and AP-1, that can be activated in mature (CD4+ CD8-TcRhigh) and immature (CD4-CD8-TcR-) thymocytes alike but not in the transitional stages when the cells (CD4+ CD8+ TcROW) are subject to selection; and (iv) a factor containing CREB, which can be activated in thymocytes of all developmental stages by culture but does not require specific induction. These results verify that inducible transcription factors are targets of intrathymic developmental change. They also identify NF-AT and AP-1 as factors that are particularly sensitive to the mechanism altering thymocyte responses during the stages when thymocytes may undergo positive and negative selection.

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Early precursor thymocytes can produce interleukin 2 upon stimulation with calcium ionophore and phorbol ester.

Cited by 43 publications

References 36 publications

Regulation of AP-1 and NFAT Transcription Factors during Thymic Selection of T Cells

Regulation of AP-1 and NFAT Transcription Factors during Thymic Selection of T Cells

Interleukin 4 is a growth factor for activated thymocytes: possible role in T-cell ontogeny.

Molecular basis for developmental changes in interleukin-2 gene inducibility.

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