CD200 is overexpressed in many solid tumors and considered as an immune checkpoint molecule dampening cancer immunity. In this study, we found that CD200R-/- mice were significantly more potent in rejecting these CD200+ tumors. scRNA sequencing demonstrated that tumors from CD200R-/- mice had more infiltration of CD4+ and CD8+ T cells, and NK cells but less infiltration of neutrophils. Antibody depletion experiments revealed that immune effector cells are crucial in inhibiting tumor growth in CD200R-/- mice. Mechanistically, we found that CD200R signaling regulates the expression of chemokines in tumor-associated myeloid cells (TAMCs). In the absence of CD200R, TAMCs increased expression of CCL24 and resulted in increased infiltration of eosinophils, which contributes to anti-tumor activity. Overall, we conclude that CD200R signaling contributes to unfavorable TME through chemokine-dependent recruitment of immune suppressive neutrophils and exclusion of anti-cancer immune effectors. Our study has implications in developing CD200-CD200R targeted immunotherapy of solid tumors.
© 2023 The Author(s).

CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms. Here, we show that effector-type regulatory T cells (Tregs) are main sCTLA-4 producers in basal and inflammatory states with distinct kinetics upon TCR stimulation. Mice specifically deficient in sCTLA-4 production exhibited spontaneous activation of Th1, Th17, Tfh, and Tc1 cells, autoantibody and IgE production, M1-like macrophage polarization, and impaired wound healing. In contrast, sCTLA-4-intact mCTLA-4-deficient mice, when compared with double-deficient mice, developed milder systemic inflammation and showed predominant activation/differentiation of Th2, M2-like macrophages, and eosinophils. Consistently, recombinant sCTLA-4 inhibited in vitro differentiation of naïve T cells towards Th1 through CD80/CD86 blockade on antigen-presenting cells, but did not affect Th2 differentiation. Moreover, sCTLA-4-intact mCTLA-4-deficient Tregs effectively suppressed Th1-mediated experimental colitis whereas double-deficient Tregs did not. Thus, sCTLA-4 production by Tregs during chronic inflammation is instrumental in controlling type 1 immunity while allowing type 2 immunity to dominate and facilitate inflammation resolution.

Pigs are the most suitable model to study various therapeutic strategies and drugs for human beings, while knowledge about tissue- and cell type-specific transcriptomes and heterogeneity is poorly available. Here, we focused on the intestinal immunity of pigs. Through single-cell sequencing (scRNA-seq) and flow cytometry analysis of the types of immune cells in the jejunum of pigs, we found that innate lymphoid cells (ILCs) existed in the lamina propria lymphocytes (LPLs) of the jejunum. Then, through flow sorting of Live/Dead (L/D) - Lineage(LIN) - CD45 + cells and scRNA-seq, we found that ILCs in the porcine jejunum were mainly ILC3s, with a small number of ILC1s, ILC2s and NK cells. Through a gene expression map, we found that ILCs coexpressed IL-7Rα, ID2 and other genes and differentially expressed RORC, GATA3 and other genes but did not express the CD3 gene. According to their gene expression profiles, ILC3s can be divided into four subgroups, and genes such as CXCL8, CXCL2, IL-22, IL-17 and NCR2 are differentially expressed. To further detect and identify ILC3s, we prepared RORC monoclonal antibodies and verified the classification of ILCs in the porcine jejunum subgroup and the expression of related hallmark genes at the protein level by flow cytometry. For systematically characterizing of ILCs in the porcin intestines, we combined our pigs ILCs dataset with publicly available humans and mice ILCs data and identified that the humans and pigs ILCs shared more common features than that of mice in gene signatures and cell states. Our results for the first time showed in detail the gene expression of porcine jejunal ILCs, the subtype classification of ILCs and the markers of various ILCs, which provides a basis for in-depth exploration of porcine intestinal mucosal immunity. Graphical abstract

Asthma is airway inflammatory diseases caused by the activation of group 2 innate lymphoid cells (ILC2s) and type 2 helper T (TH2) cells. Cysteine proteases allergen cause tissue damage to airway epithelial cells and activate ILC2-mediated type 2 airway inflammation. FK506 is an immunosuppressive agent against calcium-dependent NFAT activation that is also effective against asthmatic inflammation. However, the effects of FK506 on cysteine protease allergen-mediated airway inflammation remain unclear. In this study, we investigated the suppressive effects of FK506 on airway inflammation. FK506 had a partial inhibitory effect on ILC2-dependent eosinophil inflammation and a robust inhibitory effect on T cell-dependent eosinophil inflammation in a cysteine protease-induced mouse asthma model. The infiltration of T1/ST2+ CD4 T cells in the lungs contributed to the persistence of eosinophil infiltration in the airway; FK506 completely inhibited the infiltration of T1/ST2+ CD4 T cells. In the initial phase, FK506 treatment targeted lung ILC2 activation induced by leukotriene B4 (LTB4)-mediated calcium signaling, but not IL-33 signaling. FK506 also inhibited the IL-13-dependent accumulation of T1/ST2+ CD4 T cells in the lungs of the later responses. These results indicated that FK506 potently suppressed airway inflammation by targeting ILC2 activation and T1/ST2+ CD4 T cell accumulation.
Copyright © 2022 Tomiaki, Miyauchi, Ki, Suzuki, Suzuki, Morimoto, Mukoyama and Kubo.

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.