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Mutations affecting the Tec kinases Itk and Rlk decrease T cell receptor-induced Ca 2+ mobilization and Erk kinase activation and impair both positive and negative thymic selection. Itk −/− and Rlk −/− Itk −/− mice also have decreased CD4:8 T cell ratios, suggestive of altered CD4:8 lineage commitment. Nonetheless, we find that CD8 single-positive (SP) thymocytes and...
Histocompatibility in the primitive chordate, Botryllus schlosseri, is controlled by a single, highly polymorphic locus, the FuHC. By taking a forward genetic approach, we have identified a locus encoded near the FuHC, called fester, which is polymorphic, polygenic, and inherited in distinct haplotypes. Somatic diversification occurs through extensive alternative splicing, with each individual expressing...
The Tec family tyrosine kinases, Itk and Rlk, are expressed in thymocytes and peripheral T cells and regulate thresholds of T cell receptor signaling. Yet little is known about the specific role of Itk- and Rlk-dependent signals in CD8 + T cell maturation. We show here that Itk −/− and Rlk −/− Itk −/− mice were nearly devoid of conventional CD8 + T cells and,...
Transforming growth factor-β (TGF-β) has been implicated in the control of differentiation and proliferation of multiple cell types. However, a role for TGF-β in the control of immune homeostasis is not fully understood because of its pleiotropic action. Here we report that complete ablation of the TGF-β signaling in T cells engendered aggressive early-onset, multiorgan, autoimmune-associated lesions...
Invariant natural killer T (iNKT) cell-derived cytokines have important functions in inflammation, host defense, and immunoregulation. Yet, when and how iNKT cells undergo effector differentiation, which endows them with the capacity to rapidly secrete cytokines upon activation, remains unknown. We discovered that granulocyte-macrophage colony-stimulating factor (Csf-2)-deficient mice developed iNKT...
The role of transforming growth factor-β (TGF-β) in inhibiting T cell functions has been studied with dominant-negative TGF-β receptor transgenic models; however, the full impact of TGF-β signaling on T cells and the mechanisms by which TGF-β signals remain poorly understood. Here we show that mice with T cell-specific deletion of TGF-β receptor II developed lethal inflammation associated with T cell...
Anopheles gambiae, the major vector for the protozoan malaria parasite Plasmodium falciparum, mounts powerful antiparasitic responses that cause marked parasite loss during midgut invasion. Here, we showed that these antiparasitic defenses were composed of pre- and postinvasion phases and that the preinvasion phase was predominantly regulated by Rel1 and Rel2 members of the NF-κB transcription factors...
The differentiation potential of T lineage cells becomes restricted soon after entry of multipotent precursors into the thymus and is accompanied by a downregulation of the transcription factors C/EBPα and PU.1. To investigate this restriction point, we have expressed C/EBPα and PU.1 in fully committed pre-T cells and found that C/EBPα (and C/EBPβ) induced the formation of functional macrophages....
Although the ontogeny of hematopoietic stem cells (HSCs) in vertebrates has been studied intensely, a lineage relationship between the HSCs found in the developmentally successive hematopoietic organs remains to be shown. By using an in situ photoactivatable cell tracer in the transparent zebrafish embryo, we demonstrated that definitive blood precursors appeared between the dorsal aorta and axial...
The integrin α9β1 is widely expressed on neutrophils, smooth muscle, hepatocytes, endothelia, and some epithelia. We now show that mice lacking this integrin have a dramatic defect in neutrophil development, with decreased numbers of granulocyte precursors in bone marrow and impaired differentiation of bone marrow cells into granulocytes. In response to granulocyte colony-stimulating factor (G-CSF),...
Recent studies implicated the existence of adult lymphoid-primed multipotent progenitors (LMPPs) with little or no megakaryocyte-erythroid potential, questioning common myeloid and lymphoid progenitors as obligate intermediates in hematopoietic stem cell (HSC) lineage commitment. However, the existence of LMPPs remains contentious. Herein, global and single-cell analyses revealed a hierarchical organization...
Development of Peyer's patches and lymph nodes requires the interaction between CD4 + CD3 − IL-7Rα + lymphoid-tissue inducer (LTi) and VCAM-1 + organizer cells. Here we showed that by promoting their survival, enhanced expression of interleukin-7 (IL-7) in transgenic mice resulted in accumulation of LTi cells. With increased IL-7 availability, de novo formation of VCAM-1...
The mechanisms regulating lineage potential during early hematopoiesis were investigated. First, a cascade of lineage-affiliated gene expression signatures, primed in hematopoietic stem cells (HSCs) and differentially propagated in lineage-restricted progenitors, was identified. Lymphoid transcripts were primed as early as the HSC, together with myeloid and erythroid transcripts. Although this multilineage priming...
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