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TGFβ is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-heavy tumors. Using B16 mouse melanoma and CT26 colon carcinoma as models of stroma-poor tumors, we demonstrate that myeloid/dendritic cells are the main sources of TGFβ1 and TGFβ3. Depending on local expression of TGFβ isoforms, isoform specific inhibition of either TGFβ1 or TGFβ3 may be effective. The TGFβ signature of CT26 colon carcinoma is defined by TGFβ1 and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. Using T cell functional assays, we show that the mechanism of tumor delay is through and dependent on enhanced CD8+ T cell function. To overcome the local immunosuppressive environment, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control. Our data suggest that TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor suppression.Gupta et al. demonstrate that targeting isoform-specific TGFβ leads to an increase in the anti-tumor response when compared to pan-TGFβ inhibition, due to enhanced CD8 T cell function. The authors also report that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control.

The cellular sources of IL-9 in lung inflammation remain unknown. Stockinger and colleagues use an IL-9 reporter to show IL-9 production is restricted to innate lymphoid cells during papain-induced lung inflammation. Interleukin 9 (IL-9) is a cytokine linked to lung inflammation, but its cellular origin and function remain unclear. Here we describe a reporter mouse strain designed to map the fate of cells that have activated IL-9. We found that during papain-induced lung inflammation, IL-9 production was largely restricted to innate lymphoid cells (ILCs). IL-9 production by ILCs depended on IL-2 from adaptive immune cells and was rapidly lost in favor of other cytokines, such as IL-13 and IL-5. Blockade of IL-9 production via neutralizing antibodies resulted in much lower expression of IL-13 and IL-5, which suggested that ILCs provide the missing link between the well-established functions of IL-9 in the regulation of type 2 helper T cell cytokines and responses.

The development of T helper (TH)17 and regulatory T (Treg) cells is reciprocally regulated by cytokines. Transforming growth factor (TGF)-β alone induces FoxP3⁺ Treg cells, but together with IL-6 or IL-21 induces TH17 cells. Here we demonstrate that IL-9 is a key molecule that affects differentiation of TH17 cells and Treg function. IL-9 predominantly produced by TH17 cells, synergizes with TGF-β1 to differentiate naïve CD4⁺ T cells into TH17 cells, while IL-9 secretion by TH17 cells is regulated by IL-23. Interestingly, IL-9 enhances the suppressive functions of FoxP3⁺ CD4⁺ Treg cells in vitro, and absence of IL-9 signaling weakens the suppressive activity of nTregs in vivo, leading to an increase in effector cells and worsening of experimental autoimmune encephalomyelitis. The mechanism of IL-9 effects on TH17 and Tregs is through activation of STAT3 and STAT5 signaling. Our findings highlight a role of IL-9 as a regulator of pathogenic versus protective mechanisms of immune responses.

Infections may affect the course of autoimmune inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). Infections with lactate dehydrogenase-elevating virus (LDV) protected mice from developing experimental autoimmune encephalomyelitis (EAE), a mouse counterpart of MS. Uninfected C57BL/6 mice immunized with the myelin oligodendrocyte glycoprotein peptide (MOG35–55) experienced paralysis and lost weight at a greater rate than mice who had previously been infected with LDV. LDV infection decreased the presentation of the MOG peptide by CD11b+CD11c+ dendritic cells (DC) to pathogenic T lymphocytes. When comparing non-infected mice to infected mice, the histopathological examination of the CNS showed more areas of demyelination and CD45+ and CD3+, but not Iba1+ cell infiltration. These results suggest that the protective effect of LDV infection against EAE development is mediated by a suppression of myelin antigen presentation by a specific DC subset to autoreactive T lymphocytes. Such a mechanism might contribute to the general suppressive effect of infections on autoimmune diseases known as the hygiene hypothesis.

For effective treatments and preventive measures against severe COVID-19, it is essential to determine early markers of disease severity in different populations. We analysed the cytokine kinetics of 129 COVID-19 patients with mild symptoms, 68 severe cases, and 20 healthy controls for the first time in Rwanda. Pro-inflammatory (IFNγ, IL-6, TNFα), Treg (IL-10, TGFβ1, TGFβ3), Th9 (IL-9), Th17 (IL-17), and Th2 (IL-4, IL-13) cytokines, total IgM and IgG, as well as gene expressions of FoxP3, STAT5+, IFNγ-R1, and ROR alpha+, were measured at day 1, day 7, day 14, day 21, and day 28 post-infection. Severe cases showed a significantly stronger increase than mild patients in levels of all cytokines (except IL-9) and all gene expression on day 1 of infection. Some cytokine levels dropped to levels comparable to mild cases at later time points. Further analysis identified IFNγ as a marker of severity throughout the disease course, while TGFβ1, IL-6, and IL-17 were markers of severity only at an early phase. Importantly, this study revealed a striking low IL-9 level and high IFNγ/IL-9 ratio in the plasma of patients who later died compared to mild and severe cases who recovered, suggesting that this could be an important biomarker for predicting the severity of COVID-19 and post-COVID-19 syndrome.

Host directed immunomodulation represents potential new adjuvant therapies in infectious diseases such as tuberculosis. Major cytokines like TNFα exert a multifold role in host control of mycobacterial infections. GM-CSF and its receptor are over-expressed during acute M . tuberculosis infection and we asked how GM-CSF neutralization might affect host response, both in immunocompetent and in immunocompromised TNFα-deficient mice. GM-CSF neutralizing antibodies, at a dose effectively preventing acute lung inflammation, did not affect M . tuberculosis bacterial burden, but increased the number of granuloma in wild-type mice. We next assessed whether GM-CSF neutralization might affect the control of M . tuberculosis by isoniazid/rifampicin chemotherapy. GM-CSF neutralization compromised the bacterial control under sub-optimal isoniazid/rifampicin treatment in TNFα-deficient mice, leading to exacerbated lung inflammation with necrotic granulomatous structures and high numbers of intracellular M . tuberculosis bacilli. In vitro , GM-CSF neutralization promoted M2 anti-inflammatory phenotype in M . bovis BCG infected macrophages, with reduced mycobactericidal NO production and higher intracellular M . bovis BCG burden. Thus, GM-CSF pathway overexpression during acute M . tuberculosis infection contributes to an efficient M1 response, and interfering with GM-CSF pathway in the course of infection may impair the host inflammatory response against M . tuberculosis .

Contrary to the proinflammatory role of mast cells in allergic disorders, the results obtained in this study establish that mast cells are essential in CD4 + CD25 + Foxp3 + regulatory T (T Reg )-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of T Reg cells, acquire a unique genetic signature dominated by the expression of mast-cell-gene products. We also show that mast cells are crucial for allograft tolerance, through the inability to induce tolerance in mast-cell-deficient mice. High levels of interleukin (IL)-9—a mast cell growth and activation factor—are produced by activated T Reg cells, and IL-9 production seems important in mast cell recruitment to, and activation in, tolerant tissue. Our data indicate that IL-9 represents the functional link through which activated T Reg cells recruit and activate mast cells to mediate regional immune suppression, because neutralization of IL-9 greatly accelerates allograft rejection in tolerant mice. Finally, immunohistochemical analysis clearly demonstrates the existence of this novel T Reg –IL-9–mast cell relationship within tolerant allografts. Mast Cells and Graft Rejection Mast cells are important immune system components, best known as responders in allergic reactions such as anaphylaxis and asthma. Recent work suggests that they also act as immunoregulatory cells in both innate and adaptive immunity and surprisingly, gene expression profiles point to an association with tolerance to tissue transplants. Studies in mice now confirm that mast cells are major cellular players in immune suppression, needed for peripheral suppression dependent on regulatory T cells. This also implies a role for interleukin 9 (IL-9) as a link between activated T cells and mast cell recruitment and makes IL-9, mast cells and their gene products of interest as targets for drugs to prevent graft rejection.

Although the cytokine interleukin 9 (IL-9) was discovered decades ago, it remains one of the most enigmatic cytokines identified so far, in particular because its functional activities remain far from clear. Breakthroughs made through the use of IL-9 reporter mice have allowed the identification of cell types that produce IL-9 in vivo and, contrary to expectations based on previous results obtained in vitro , it is not T cells but instead a previously unknown type of innate lymphoid cell, called the 'ILC2 cell', that is the main cell type that expresses IL-9 in vivo . In this perspective, we put forward a hypothesis about the potential biological functions of IL-9 in the immune system and beyond.

Airborne ozone exposure causes severe lung injury and inflammation. The aryl hydrocarbon Receptor (AhR) (1), activated in pollutant-induced inflammation, is critical for cytokine production, especially IL-22 and IL-17A. The role of AhR in ozone-induced lung inflammation is unknown. We report here that chronic ozone exposure activates AhR with increased tryptophan and lipoxin A4 production in mice. AhR mice show increased lung inflammation, airway hyperresponsiveness, and tissue remodeling with an increased recruitment of IL-17A and IL-22-expressing cells in comparison to control mice. IL-17A- and IL-22-neutralizing antibodies attenuate lung inflammation in AhR and control mice. Enhanced lung inflammation and recruitment of ILC3, ILC2, and T cells were observed after T cell-specific AhR depletion using the AhR -deficient mice. Together, the data demonstrate that ozone exposure activates AhR, which controls lung inflammation, airway hyperresponsiveness, and tissue remodeling via the reduction of IL-22 expression.

Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL + ) cells. Renal tumors with either VHL + or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL + cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL − ) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.