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Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFβ signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFβ signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFβ-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and -extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal. Ageing of the haematopoietic system is accompanied by declining erythropoiesis and lymphopoiesis. Here the authors uncover upregulated IL-6 and TGFβ signalling in aged bone marrow stroma; inhibition of these signals reverses age-related haematopoietic defects, re-balancing haematopoietic stem cell lineage output.

Activation of mTOR-dependent pathways regulates the specification and differentiation of CD4+ T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) and mTORC2 have distinct roles in the generation of CD8+ T cell effector and memory populations. Evaluation of mice with a T cell-specific deletion of the gene encoding the negative regulator of mTORC1, tuberous sclerosis complex 2 (TSC2), resulted in the generation of highly glycolytic and potent effector CD8+ T cells; however, due to constitutive mTORC1 activation, these cells retained a terminally differentiated effector phenotype and were incapable of transitioning into a memory state. In contrast, CD8+ T cells deficient in mTORC1 activity due to loss of RAS homolog enriched in brain (RHEB) failed to differentiate into effector cells but retained memory characteristics, such as surface marker expression, a lower metabolic rate, and increased longevity. However, these RHEB-deficient memory-like T cells failed to generate recall responses as the result of metabolic defects. While mTORC1 influenced CD8+ T cell effector responses, mTORC2 activity regulated CD8+ T cell memory. mTORC2 inhibition resulted in metabolic reprogramming, which enhanced the generation of CD8+ memory cells. Overall, these results define specific roles for mTORC1 and mTORC2 that link metabolism and CD8+ T cell effector and memory generation and suggest that these functions have the potential to be targeted for enhancing vaccine efficacy and antitumor immunity.

The role of the repressors Bach1 and Bach2 in early B cell development is unclear. Igarashi and colleagues have now found these Bach factors directly repress various myeloid genes in common lymphoid progenitors to restrict a B cell lineage fate. Mature lymphoid cells express the transcription repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B lineage, commencing from the common lymphoid progenitor (CLP) stage, with Bach1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and Bach1 repressed the expression of genes important for myeloid cells ('myeloid genes'). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2 hi CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with Bach1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs.

A rodent model of diet-induced obesity revealed that obesity significantly altered hematopoietic and lymphopoietic functions in the bone marrow and thymus. C57BL/6 mice were fed a mixed high-fat diet (HFD) of 45% fat or 10% fat diet (lean controls) for 180 d. A sustained increase in the numbers of cells found in bone marrow and thymus of HFD mice occurred from day 90 to day 180. However, with the exception of a 10–18% increase in the proportion of lymphocytes, the composition of monocytes, granulocytes, erythrocytes, and mixed progenitor lineages remained normal in the marrow. Likewise, thymuses of HFD mice increased 30–50% in size compared with controls, with analogous increases in thymocyte numbers. The overall thymus cellular composition remained normal. Although increased blood and lymphatic volume in obese mice would play a role in increased hematopoiesis, there were large and disproportionate increases in blood leukocytes of HFD mice, indicating that homeostasis was not maintained. Leptin, which promotes lymphopoiesis and myelopoiesis, reached 100 ng/mL in sera from HFD mice. Moreover, a three- to sixfold increase in adipocytes in marrow resulted in spiked leptin mRNA expression in bones of HFD mice compared with lean controls. Other cytokines and growth factors did not show any increases in obese marrow. The substantial increase in lymphopoietic and hematopoietic processes in HFD mice indicates that the primary tissues are another facet of the immune system dysregulated by obesity, which was perhaps fostered by higher amounts of leptin in marrow and serum.

Hematopoietic stem cell (HSC) transplantation offers a cure for a variety of blood disorders, predominantly affecting the elderly; however, its application, especially in this demographic, is limited by treatment toxicity. In response, we employ a murine transplantation model based on low-intensity conditioning protocols using antibody-mediated HSC depletion. While aging presents a significant barrier to effective HSC engraftment, optimizing HSC doses and non-genotoxic targeting methods greatly enhance the long-term multilineage activity of the transplanted cells. We demonstrate that young HSCs, once effectively engrafted in aged hosts, improve hematopoietic output and ameliorate age-compromised lymphopoiesis. This culminated in a strategy that robustly mitigates disease progression in a genetic model of myelodysplastic syndrome. These results suggest that non-genotoxic HSC transplantation could fundamentally change the clinical management of age-associated hematological disorders, offering a prophylactic tool to delay or even prevent their onset in elderly patients. Konturek-Ciesla et al show that low intensity conditioning with antibody mediated haematopoietic stem cell (HSC) depletion coupled to HSC transplantation boosts blood cell and immune cell generation in aging mice, slowing disease. This approach may help treat age-related blood disorders in humans.

Pax5 controls the identity and development of B cells by repressing lineage‐inappropriate genes and activating B‐cell‐specific genes. Here, we used genome‐wide approaches to identify Pax5 target genes in pro‐B and mature B cells. In these cell types, Pax5 bound to 40% of the cis ‐regulatory elements defined by mapping DNase I hypersensitive (DHS) sites, transcription start sites and histone modifications. Although Pax5 bound to 8000 target genes, it regulated only 4% of them in pro‐B and mature B cells by inducing enhancers at activated genes and eliminating DHS sites at repressed genes. Pax5‐regulated genes in pro‐B cells account for 23% of all expression changes occurring between common lymphoid progenitors and committed pro‐B cells, which identifies Pax5 as an important regulator of this developmental transition. Regulated Pax5 target genes minimally overlap in pro‐B and mature B cells, which reflects massive expression changes between these cell types. Hence, Pax5 controls B‐cell identity and function by regulating distinct target genes in early and late B lymphopoiesis. Genome‐wide sequencing approaches reveal that the transcription factor Pax5 controls the identity and function of B cells by regulating the expression of distinct target genes in pro‐B and mature B cells.

After birth, the development of hematopoietic cells occurs in the bone marrow. Hematopoietic differentiation is finely tuned by cell-intrinsic mechanisms and lineage-specific transcription factors. However, it is now clear that the bone marrow microenvironment plays an essential role in the maintenance of hematopoietic stem cells (HSC) and their differentiation into more mature lineages. Mesenchymal and endothelial cells contribute to a protective microenvironment called hematopoietic niches that secrete specific factors and establish a direct contact with developing hematopoietic cells. A number of recent studies have addressed in mouse models the specific molecular events that are involved in the cellular crosstalk between hematopoietic subsets and their niches. This has led to the concept that hematopoietic differentiation and commitment towards a given hematopoietic pathway is a dynamic process controlled at least partially by the bone marrow microenvironment. In this review, we discuss the evolving view of murine hematopoietic–stromal cell crosstalk that is involved in HSC maintenance and commitment towards B cell differentiation.

Lifelong mammalian hematopoiesis requires continuous generation of mature blood cells that originate from Hematopoietic Stem and Progenitor Cells (HSPCs) situated in the post-natal Bone Marrow (BM). The BM microenvironment is inherently complex and extensive studies have been devoted to identifying the niche that maintains HSPC homeostasis and supports hematopoietic potential. The Notch signaling pathway is required for the emergence of the definitive Hematopoietic Stem Cell (HSC) during embryonic development, but its role in BM HSC homeostasis is convoluted. Recent work has begun to explore novel roles for the Notch signaling pathway in downstream progenitor populations. In this review, we will focus an important role for Notch signaling in the establishment of a T cell primed sub-population of Common Lymphoid Progenitors (CLPs). Given that its activation mechanism relies primarily on cell-to-cell contact, Notch signaling is an ideal means to investigate and define a novel BM lymphopoietic niche. We will discuss how new genetic model systems indicate a pre-thymic, BM-specific role for Notch activation in early T cell development and what this means to the paradigm of lymphoid lineage commitment. Lastly, we will examine how leukemic T-cell acute lymphoblastic leukemia (T-ALL) blasts take advantage of Notch and downstream lymphoid signals in the pathological BM niche.

Recent studies by Dorshkind, Yoder, and colleagues show that embryonic (E9) B-cell progenitors located in the yolk sac and intraembryonic hemogenic endothelium before the initiation of circulation give rise to B-1 and marginal zone B cells but do not give rise to B-2 cells. In studies here, we confirm and extend these findings by showing that distinct progenitors for B-1 and B-2 cells are present in the adult spleen. Furthermore, we show that the splenic B-cell progenitor population (lin⁻CD19⁺/B220lo/⁻/CD43⁻) that gives rise to B-1 cells is likely to be heterogeneous because, in some recipients, it also gives rise to B cells expressing the marginal zone phenotype (B220hiIgMhiIgDloCD21hi) and to some (CD19⁻CD5hi) T cells. In addition to the well-known function differences between B-1 and B-2, our studies demonstrate that substantial developmental differences separate these B-cell lineages. Thus, consistent with the known dependence of B-2 development on IL-7, all B-2 progenitors express IL-7R. However, >30% of the B-1 progenitors do not express this marker, enabling the known IL-7 independent development of B-1 cells in IL-7⁻/⁻ mice. In addition, marker expression on cells in the early stages of the B-2 development pathway (CD19⁻/c-Kitlo/⁻/Sca-1lo/⁻) in adult bone marrow distinguish it from the early stages of B-1 development (CD19hi/c-Kit⁺/Sca-1⁺), which occur constitutively in neonates. In adults, in vivo inflammatory stimulation (LPS) triggers B-1 progenitors in spleen to expand and initiate development along this B-1 developmental pathway.

Bone marrow (BM) produces all blood and immune cells deriving from hematopoietic stem cells (HSCs). The decrease of immune cell production during aging is one of the features of immunosenescence. The impact of redox dysregulation in BM aging is still poorly understood. Here we use TP53INP1-deficient (KO) mice endowed with chronic oxidative stress to assess the influence of aging-associated redox alterations in BM homeostasis. We show that TP53INP1 deletion has no impact on aging-related accumulation of HSCs. In contrast, the aging-related contraction of the lymphoid compartment is mitigated in TP53INP1 KO mice. B cells that accumulate in old KO BM are differentiating cells that can mature into functional B cells. Importantly, this phenotype results from B cell-intrinsic events associated with defective redox control. Finally, we show that oxidative stress in aged TP53INP1-deficient mice maintains STAT5 expression and activation in early B cells, driving high Pax5 expression, which provides a molecular mechanism for maintenance of B cell development upon aging.