During B lymphopoiesis, Igk recombination requires pre-B cell receptor (pre-BCR) expression and escape from interleukin 7 receptor (IL-7R) signaling. By activating the transcription factor STAT5, IL-7R signaling maintains proliferation and represses Igk germline transcription by unknown mechanisms. We demonstrate that STAT5 tetramer bound the Igk intronic enhancer (Eκi), leading to recruitment of the histone methyltransferase Ezh2. Ezh2 marked H3K27me3 throughout Jκ to Cκ. In the absence of Ezh2, IL-7 failed to repress Igk germline transcription. H3K27me3 modifications were lost after termination of IL-7R–STAT5 signaling and E2A bound Eκi, resulting in acquisition of H3K4me1 and H4Ac. Genome-wide analyses revealed a STAT5 tetrameric binding motif associated with transcriptional repression. These data demonstrate how IL-7R signaling represses Igk germline transcription and provide a general model for STAT5-mediated epigenetic transcriptional repression.
Signals through the pre-B cell antigen receptor (pre-BCR) and IL-7 receptor (IL-7R) coordinate pre-B cell expansion with subsequent Igκ recombination. While many downstream effectors of each receptor are known, how they integrate to mediate development has remained unclear. Herein, we report that pre-BCR mediated activation of the Ras/MEK/ERK signaling pathway silences Ccnd3 transcription and coordinates cell cycle exit with the induction of E2A and the initiation of Igκ recombination. These activities are opposed by IL-7R mediated STAT 5 activation which promotes Ccnd3 expression and concomitantly inhibits Igκ transcription by binding to E κi and inhibiting E2A recruitment. Our data reveal how pre-BCR signaling poises pre-B cells to undergo differentiation upon escape from IL-7R signaling.
During hematopoiesis, stem cell proliferation is dependent on expression of the D-type cyclins. However, little is known about how each cyclin D contributes to the development of specific hematopoietic lineages. Here, analysis of Ccnd1(-/-), Ccnd2(-/-), Ccnd3(-/-) and Ccnd2(-/-)Ccnd3(-/-) mice showed that cyclin D3 was uniquely required for the development of pre-B cells. Transcription of Ccnd3 was dependent on expression of the common gamma-chain. In contrast, expression of the pre-B cell receptor and activation of 'downstream' signaling pathways prevented proteasome-mediated degradation of cyclin D3. Cyclin D3 has a key function in B cell development by integrating cytokine and pre-B cell receptor-dependent signals to expand the pool of pre-B cells that have successfully rearranged immunoglobulin heavy chain.
Investigations regarding the incorporation of better sustainable production strategies into current agricultural-food systems are necessary to grow crops that reduce negative impacts on the environment yet will meet the production and nutritional demand of 10 billion people by 2050. The introduction of organic, alternative staple food crops, such as nutrient-dense field pea (Pisum sativum L.), to the everyday diet, may alleviate micronutrient malnutrition and incorporate more sustainable agriculture practices globally. Varieties are grown in organic systems currently yield less than conventionally produced foods, with less bioavailable nutrients, due to poor soil nutrient content. One of the most limiting nutrients for field pea is phosphorus (P) because this legume crop requires significant inputs for nodule formation. Therefore, P use efficiency (PUE) should be a breeding target for sustainable agriculture and biofortification efforts; the important role of the soil microbiome in nutrient acquisition should also be examined. The objectives of this review are to highlight the benefits of field pea for organic agriculture and human health, and discuss nutritional breeding strategies to increase field pea production in organic systems. Field pea and other pulse crops are underrepresented in agricultural research, yet are important crops for a sustainable future and better food systems. Furthermore, because field pea is consumed globally by both developed and at-risk populations, research efforts could help increase global health overall and combat micronutrient malnutrition.
T cells are essential for immune defenses against pathogens, such that viability of naïve T cells before antigen encounter is critical to preserve a polyclonal repertoire and prevent immunodeficiencies. The viability of naïve T cells before antigen recognition is ensured by IL-7, which drives expression of the prosurvival factor Bcl-2. Quiescent naïve T cells have low basal activity of the transcription factor NF-κB, which was assumed to have no functional consequences. In contrast to this postulate, our data show that basal nuclear NF-κB activity plays an important role in the transcription of IL-7 receptor α-subunit (CD127), enabling responsiveness of naïve T cells to the prosurvival effects of IL-7 and allowing T-cell persistence in vivo. Moreover, we show that this property of basal NF-κB activity is shared by mouse and human naïve T cells. Thus, NF-κB drives a distinct transcriptional program in T cells before antigen encounter by controlling susceptibility to IL-7. Our results reveal an evolutionarily conserved role of NF-κB in T cells before antigenic stimulation and identify a novel molecular pathway that controls T-cell homeostasis.urvival of naïve quiescent T cells is essential to maintain a pool of polyclonal T cells ready for activation by their cognate antigen. On egress from the thymus, survival of peripheral naïve T cells (CD4 + CD44 lo and CD8 + CD44 lo ) depends on intermittent tonic engagement of the T-cell receptor (TCR) and signaling by the cytokine IL-7 (1, 2). Tonic TCR engagement is generated by the interaction of the TCR with weakly reactive self-peptides (3). Survival of quiescent CD8 T cells requires MHC class I-TCR engagement, which is indicated by dwindling numbers of naïve CD8 T cells after transfer into MHC class I-deficient mice (4, 5). In addition, long-term (but not short-term) survival of CD4 T cells requires the presence of MHC class II (6).IL-7 is important for survival and homeostatic proliferation of naïve T cells, which is shown by reduced recovery of naïve T cells transferred into IL-7 −/− mice (7, 8) and impaired survival and homeostatic proliferation of T cells from IL-7 receptor α-subunit (IL-7Rα) -deficient mice (9, 10). The receptor for IL-7 is a heterodimer consisting of the IL-7Rα (CD127) and common γ-chain receptor (γ c ; CD132) subunits. Triggering of IL-7R activates Stat5 through Jak1/Jak3 (11) and the PI3K/Akt/mTOR axis (12). IL-7-mediated survival involves up-regulation of the prosurvival factors Bcl-2 and Mcl-1 as well as reduction of proapoptotic molecules Bax, Bad, and Bim (13). Interestingly, IL-7 negatively regulates the expression of its receptor, promoting endocytosis, degradation, and the transcriptional inhibition of Il7r expression (11,14). This milieu enables a pool of T cells that have not yet encountered IL-7 to be preferentially responsive to limiting concentrations of this cytokine. Several transcription factors are involved in the control of Il7r expression in T cells, including positive regulation by GA binding protein, glucocorticoid receptor,...
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