Lee and colleagues investigated the role of the intestinal microbiota in steady-state hematopoieisis, demonstrating that microbiota-derived DNA circulates to the bone marrow, where uptake by mononuclear cells leads to inflammatory cytokine production favoring myeloid-cell maturation of hematopoietic progenitors.

Stratification of asthmatic patients based on relevant biomarkers enables the prediction of responsiveness against immune-targeted therapies in patients with asthma. Individualised therapy in patients with eosinophilic asthma has yielded improved clinical outcomes; similar approaches in patients with neutrophilic asthma have yet to be developed. We determined whether colony-stimulating factors (CSFs) in the airway reflect the inflammatory phenotypes of asthma and contribute to disease progression of neutrophilic asthma.We analysed three different mouse models of asthma and assessed cytokine profiles in sputum from human patients with asthma stratified according to inflammatory phenotype. In addition, we evaluated the therapeutic efficacy of various cytokine blockades in a mouse model of neutrophilic asthma.Among the CSFs, airway granulocyte CSF (G-CSF) contributes to airway neutrophilia by promoting neutrophil development in bone marrow and thereby distinguishes neutrophilic inflammation from eosinophilic inflammation in mouse models of asthma. G-CSF is produced by concurrent stimulation of the lung epithelium with interleukin (IL)-17A and tumour necrosis factor (TNF)-α; therefore, dual blockade of upstream stimuli using monoclonal antibodies or genetic deficiency of the cytokines in IL-17A×TNF-α double-knockout mice reduced the serum level of G-CSF, leading to alleviation of neutrophilic inflammation in the airway. In humans, the sputum level of G-CSF can be used to stratify patients with asthma with neutrophil-dominated inflammation.Our results indicated that myelopoiesis-promoting G-CSF and cytokines as the upstream inducing factors are potential diagnostic and therapeutic targets in patients with neutrophilic asthma.

Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB–dependent antitumor response in hB7-H3–overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1+Tim-3+ “terminally differentiated” subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB–expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3–positive cancers as monotherapy and combination therapy with PD-1 blockade.

Conventional CD4+ T cells are differentiated into CD4+CD8αα+ intraepithelial lymphocytes (IELs) in the intestine; however, the roles of intestinal epithelial cells (IECs) are poorly understood. Here, we showed that IECs expressed MHC class II (MHC II) and programmed death–ligand 1 (PD-L1) induced by the microbiota and IFN-γ in the distal part of the small intestine, where CD4+ T cells were transformed into CD4+CD8αα+ IELs. Therefore, IEC-specific deletion of MHC II and PD-L1 hindered the development of CD4+CD8αα+ IELs. Intracellularly, PD-1 signals supported the acquisition of CD8αα by down-regulating the CD4-lineage transcription factor, T helper–inducing POZ/Krüppel-like factor (ThPOK), via the Src homology 2 domain–containing tyrosine phosphatase (SHP) pathway. Our results demonstrate that noncanonical antigen presentation with cosignals from IECs constitutes niche adaptation signals to develop tissue-resident CD4+CD8αα+ IELs.

Hematopoietic stem and progenitor cells (HSPCs) can produce all kind of blood lineage cells, and gut microbiota that consists of various species of microbe affects development and maturation of the host immune system including gut lymphoid cells and tissues. However, the effect of altered gut microbiota composition on homeostasis of HSPCs remains unclear. Here we show that compositional change of gut microbiota affects homeostasis of HSPCs using Rag1-/- mice which represent lymphopenic condition. The number and proportions of HSPCs in Rag1-/- mice are lower compared to those of wild types. However, the number and proportions of HSPCs in Rag1-/- mice are restored as the level of wild types through alteration of gut microbiota diversity via transferring feces from wild types. Gut microbiota composition of Rag1-/- mice treated with feces from wild types shows larger proportions of family Prevotellaceae and Helicobacterceae whereas lower proportions of family Lachnospiraceae compared to unmanipulated Rag1-/- mice. In conclusion, gut microbiota composition of lymphopenic Rag1-/- mice is different to that of wild type, which may lead to altered homeostasis of HSPCs.