Pre-TCR signaling regulates IL7 receptor α expression promoting thymocyte survival at the transition from the double-negative to double-positive stage (original) (raw)
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Immunology, 2013
Among the milestones that occur during T-cell development in the thymus is the expression of T-cell receptor-b (TCR-b) and the formation of the pre-TCR complex. Signals emanating from the pre-TCR trigger survival, proliferation and differentiation of T-cell precursors. Although the pre-TCR is essential for these cell outcomes, other receptors, such as Notch and CXCR4, also contribute. Whether interleukin-7 (IL-7) participates in promoting the survival or proliferation of pre-TCR-expressing cells is controversial. We used in vitro and in vivo models of T-cell development to examine the function of IL-7 in TCR-b-expressing thymocytes. Culturing TCR-b-expressing CD4 − CD8 − double-negative thymocytes in an in vitro model of T-cell development revealed that IL-7 reduced the frequency of CD4 + CD8 + double-positive thymocytes at the time of harvest. The mechanism for this change in the percentage of double-positive cells was that IL-7 promoted the survival of thymocytes that had not yet differentiated. By preserving the double-negative population, IL-7 reduced the frequency of double-positive thymocytes. Interleukin-7 was not required for proliferation in the in vitro system. To follow this observation, we examined mice lacking CD127 (IL-7Ra). In addition to the known effect of CD127 deficiency on T-cell development before TCR-b expression, CD127 deficiency also impaired the development of TCR-b-expressing double-negative thymocytes. Specifically, we found that Bcl-2 expression and cell cycle progression were reduced in TCR-b-expressing double-negative thymocytes in mice lacking CD127. We conclude that IL-7 continues to function after TCR-b is expressed by promoting the survival of TCR-b-expressing doublenegative thymocytes.
Journal of Experimental Medicine, 2004
Intrathymic T cell development depends on signals transduced by both T cell receptor and cytokine receptors. Early CD4 Ϫ CD8 Ϫ (double negative) thymocytes require interleukin (IL)-7 receptor (IL-7R) signals for survival and proliferation, but IL-7R signals are normally extinguished by the immature single positive (ISP) stage of thymocyte development. We now demonstrate that IL-7R signals inhibit expression of transcription factors TCF-1, LEF-1, and ROR ␥ t that are required for the ISP to double positive (DP) transition in the thymus. In addition, we demonstrate that IL-7R signals also inhibit TCF-1 and LEF-1 expression in mature peripheral T cells. Thus, the present work has identified several important downstream target genes of IL-7R signaling in T cells and thymocytes that provide a molecular mechanism for the inhibitory influence of IL-7R signaling on DP thymocyte development. We conclude that IL-7R signals down-regulate transcription factors required for the ISP to DP transition and so must be terminated by the ISP stage of thymocyte development.
Overexpression of IL-7Rα provides a competitive advantage during early T-cell development
Blood, 2004
Critical checkpoints controlling early thymic T-cell development and homeostasis are set by the proper signaling function of the interleukin 7 receptor (IL-7R) and the pre–T-cell antigen receptor. Although αβ T-cell development is observed in IL-7– and IL-7Rα–deficient mice, the number of thymocytes is significantly reduced, implying a role for the IL-7R in controlling the size of the thymic T-cell compartment. Here, we report the overexpression of IL-7Rα that occurs in the early T-cell compartment from AKR/J mice, animals that are highly susceptible to the spontaneous development of thymoma. Increased IL-7Rα was revealed by surface staining, and increased IL-7Rα mRNA was documented by using reverse transcriptase–polymerase chain reaction (RT-PCR). This resulted in increased survival of AKR/J early thymocytes, shown by the decreased frequency of TUNEL+ (terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate [dUTP]–fluorescein nick end labeling) cells. In an in vivo...
Dynamic regulation of IL-7 receptor expression is required for normal thymopoiesis
Blood, 2004
IL-7 receptor (IL-7R) levels are tightly controlled during ontogeny: high on DN cells, absent on DP cells, and high once again on thymocytes undergoing positive selection. To determine if loss of IL-7-mediated survival signals in DP cells is necessary for normal antigen-specific selection, we created T-lineage specific IL-7R α chain (IL-7Rα) transgenic (Tg) mice in which IL-7R is expressed throughout ontogeny. There was no effect of the IL-7Rα Tg on negative selection. Surprisingly, however, although the thymi of IL-7Rα Tg mice were comparable at birth, there was a decrease in thymocyte number as the mice aged. This was found to be due to competition between DN and IL-7Rexpressing DP cells for endogenous IL-7, which resulted in decreased levels of Bcl-2 in DN cells, increased DN apoptosis, and decreased DN cell number. Therefore, the downregulation of IL-7R on DP cells is an "altruistic" act required for maintaining an adequate supply of local IL-7 for DN cells.
IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte β-selection
Nature Immunology, 2015
Signaling via the pre-T cell antigen receptor (pre-TCR) and the receptor Notch1 induces transient self-renewal (b-selection) of TCRb + CD4 − CD8 − double-negative stage 3 (DN3) and DN4 progenitor cells that differentiate into CD4 + CD8 + double-positive (DP) thymocytes, which then rearrange the locus encoding the TCR a-chain (Tcra). Interleukin 7 (IL-7) promotes the survival of TCRb − DN thymocytes by inducing expression of the pro-survival molecule Bcl-2, but the functions of IL-7 during b-selection have remained unclear. Here we found that IL-7 signaled TCRb + DN3 and DN4 thymocytes to upregulate genes encoding molecules involved in cell growth and repressed the gene encoding the transcriptional repressor Bcl-6. Accordingly, IL-7-deficient DN4 cells lacked trophic receptors and did not proliferate but rearranged Tcra prematurely and differentiated rapidly. Deletion of Bcl6 partially restored the self-renewal of DN4 cells in the absence of IL-7, but overexpression of BCL2 did not. Thus, IL-7 critically acts cooperatively with signaling via the pre-TCR and Notch1 to coordinate proliferation, differentiation and Tcra recombination during b-selection.
Cell-fate decisions in early T cell development: regulation by cytokine receptors and the pre-TCR
Seminars in Immunology, 1999
During lymphocyte development, cell-fate decisions are determined by a myriad of signals produced by the microenvironment of the thymus and the bone marrow. These yet to be fully defined developmental cues regulate stage-specific gene expression, and the extraordinarily well-characterized stages of T and B cell development have provided attractive model systems for studying regulation of cellular differentia-
Differential IL-7 responses in developing human thymocytes
Human Immunology, 2010
IL-7 is a factor essential for mouse and human thymopoiesis. Mouse thymocytes have altered sensitivities to IL-7 at different developmental stages. CD4/CD8 double positive (DP) mouse thymocytes are shielded from the influence of IL-7 due to loss of CD127 (IL-7Rα). In this study, we assessed IL-7 receptor expression and IL-7 signaling in human thymocytes. We found human DP cells to be severely limited in their ability to phosphorylate STAT-5 in response to IL-7. The relative expression levels of the IL-7-inducible proteins Bcl-2 and Mcl-1 were also lower in human DP cells, consistent with a stage-specific decrease in IL-7 responsiveness. IL-7 responses were restored in a subset of cells that matured past the DP stage. Unlike the regulation of IL-7 signaling in mouse thymocytes, loss of IL-7 signaling in human DP cells was not due to absence of CD127 but instead correlated with downregulation of CD132 (common γ chain).