A novel sequence discovered in a computational screen appears distantly related to the p35 subunit of IL-12. This factor, which we term p19, shows no biological activity by itself; instead, it combines with the p40 subunit of IL-12 to form a novel, biologically active, composite cytokine, which we term IL-23. Activated dendritic cells secrete detectable levels of this complex. IL-23 binds to IL-12R beta 1 but fails to engage IL-12R beta 2; nonetheless, IL-23 activates Stat4 in PHA blast T cells. IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low)) T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population. Similar to IL-12, human IL-23 stimulates IFN-gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells.

OX2 (CD200) is a broadly expressed membrane glycoprotein, shown here to be important for regulation of the macrophage lineage. In mice lacking CD200, macrophage lineage cells, including brain microglia, exhibited an activated phenotype and were more numerous. Upon facial nerve transection, damaged CD200-deficient neurons elicited an accelerated microglial response. Lack of CD200 resulted in a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Outside the brain, disruption of CD200-CD200 receptor interaction precipitated susceptibility to collagen-induced arthritis (CIA) in mice normally resistant to this disease. Thus, in diverse tissues OX2 delivers an inhibitory signal for the macrophage lineage.

Human group 1 ILCs consist of at least three phenotypically distinct subsets, including NK cells, CD127(+) ILC1, and intraepithelial CD103(+) ILC1. In inflamed intestinal tissues from Crohn's disease patients, numbers of CD127(+) ILC1 increased at the cost of ILC3. Here we found that differentiation of ILC3 to CD127(+) ILC1 is reversible in vitro and in vivo. CD127(+) ILC1 differentiated to ILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1β dependent on the transcription factor RORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed in resection specimen from Crohn's disease patients a higher proportion of CD14(+) dendritic cells (DC), which in vitro promoted polarization from ILC3 to CD127(+) ILC1. In contrast, CD14(-) DCs promoted differentiation from CD127(+) ILC1 toward ILC3. These observations suggest that environmental cues determine the composition, function, and phenotype of CD127(+) ILC1 and ILC3 in the gut.

Type 2 innate lymphoid cells (ILC2s) are part of a large family of ILCs that are important effectors in innate immunity, lymphoid organogenesis, and tissue remodeling. ILC2s mediate parasite expulsion but also contribute to airway inflammation, emphasizing the functional similarity between these cells and Th2 cells. Consistent with this, we report that the transcription factor GATA3 was highly expressed by human ILC2s. CRTH2(+) ILC2s were enriched in nasal polyps of patients with chronic rhinosinusitis, a typical type 2-mediated disease. Nasal polyp epithelial cells expressed TSLP, which enhanced STAT5 activation, GATA3 expression, and type 2 cytokine production in ILC2s. Ectopic expression of GATA3 in Lin(-)CD127(+)CRTH2(-) cells resulted in induction of CRTH2 and the capacity to produce high amounts of type 2 cytokines in response to TSLP plus IL-33. Hence, we identify GATA3, potently regulated by TSLP, as an essential transcription factor for the function of human ILC2s.

The lymphocytes, T, B, and NK cells, and a proportion of dendritic cells (DCs) have a common developmental origin. Lymphocytes develop from hematopoietic stem cells via common lymphocyte and various lineage-restricted precursors. This review discusses the current knowledge of human lymphocyte development and the phenotypes and functions of the rare intermediate populations that together form the pathways of development into T, B, and NK cells and DCs. Clearly, development of hematopoietic cells is supported by cytokines. The studies of patients with genetic deficiencies in cytokine receptors that are discussed here have illuminated the importance of cytokines in lymphoid development. Lineage decisions are under control of transcription factors, and studies performed in the past decade have provided insight into transcriptional control of human lymphoid development, the results of which are summarized and discussed in this review.

Key Points Chemotherapy and radiotherapy deplete ILCs from the blood; ILC reconstitution after allogeneic HSCT is slow. High frequencies of activated ILCs with tissue homing potential before allogeneic HSCT are associated with reduced risk for GVHD.

Bipotential T/natural killer (NK) progenitor cells are present in the human thymus. Despite their bipotential capacity, these progenitors develop predominantly to T cells in the thymus. The mechanisms controlling this developmental choice are unknown. Here we present evidence that a member(s) of the family of basic helix loop helix (bHLH) transcription factors determines lineage specification of NK/T cell progenitors. The natural dominant negative HLH factor Id3, which blocks transcriptional activity of a number of known bHLH factors, was expressed in CD34+ progenitor cells by retrovirus-mediated gene transfer. Constitutive expression of Id3 completely blocks development of CD34+ cells into T cells in a fetal thymic organ culture (FTOC). In contrast, development into NK cells in an FTOC is enhanced. Thus, the activity of a bHLH transcription factor is necessary for T lineage differentiation of bipotential precursors, in the absence of which a default pathway leading to NK cell development is chosen. Our results identify a molecular switch for lineage specification in early lymphoid precursors of humans.

Tumor suppressor p53 plays an important role in regulating cell cycle progression and apoptosis. Here we applied RNA interference to study the role of p53 in human hematopoietic development in vivo. An siRNA construct specifically targeting the human tumor-suppressor gene p53 was introduced into human CD34 ؉ progenitor cells by lentivirus-mediated gene transfer, which resulted in more than 95% knockdown of p53. We adapted the human-SCID mouse model to opti- IntroductionThe tumor suppressor p53 plays an important role in regulating the cell cycle and apoptosis in response to DNA damage caused by irradiation or exposure to genotoxic mediators. In addition, p53 can mediate several cellular responses, including cell cycle arrest, senescence, differentiation, and apoptosis, depending on the cell type and the microenvironment. 1 Although mutations occur in the gene encoding p53 in human cancers, including tumors of hematopoietic origin, its function in normal human hematopoietic development remains largely unexplored.Recently, we obtained evidence that p53 plays a role in regulating the replicative lifespan of mature human T cells in vitro through the suppression of human telomerase reverse transcriptase (hTERT) (R.G., E.W., R. Beijersbergen, and H.S., manuscript in preparation). Telomeres are DNA repeats at the distal ends of the chromosomes that protect against chromosome end-to-end fusion. 2 Telomeres are shortened at each cell division, and cells with critically short telomeres undergo cell cycle arrest and become senescent. [3][4][5] hTERT, which prevents telomere shortening, is transiently up-regulated in T cells on stimulation through the T-cell receptor (TCR), 4,5 and expression of a dominant-negative mutant of hTERT significantly decreased the lifespan of CD4 ϩ and CD8 ϩ T cells, 5 indicating that hTERT plays a regulatory role in the lifespan of human T cells. Recently, we observed that the down-regulation of p53 by RNA interference (RNAi) extends the lifespan of mature human T cells and neutralizes the inhibition by dominant-negative hTERT, indicating that p53 regulates hTERT expression in primary human T cells. Given the function of p53 in mature human T cells, we asked whether the p53 loss would affect the homeostatic proliferation of T cells. Mice deficient in p53 did not show obvious defects in T-cell homeostasis. However, T cells from inbred mouse strains have longer telomeres than T cells from humans, resulting in a delay in the onset of replicative senescence and in an extended lifespan of these murine T cells. It is, therefore, of interest to test the effect of p53 inactivation on human T-cell homeostasis.In addition, we examined the role of p53 in thymic T-cell development because studies in the mouse have revealed that p53 is induced after the initiation of TCR rearrangement 6 and that it plays an important role in early T-cell development, specifically in pre-T-cell receptor signaling. 7 Results obtained in mice cannot always be extrapolated to humans, and the role of p53 in human T-cell developm...