, inflammation-mediated severe lung damage and defective haemostasis are the main underlying reasons for morbidity and mortality in coronavirus disease 2019 (COVID-19) patients [1]. Several immunotherapies that target various inflammatory processes have been successfully used in COVID-19 patients and many other strategies are under evaluation [2, 3]. However, in view of dysregulated immune responses in severe COVID-19 patients, we suggest that CD4 + CD25 + FoxP3 + regulatory T-cell (Treg)-based strategies could be considered for patient management. Vigorous antimicrobial responses triggered against the pathogen can be detrimental to the host due to collateral tissue damage. Therefore, regulatory mechanisms, and in particular Tregs, are in place to ensure that inflammation is kept in check. Tregs are either thymus-derived or induced in the periphery and are classically known for stimulating immune tolerance, and preventing autoimmune and inflammatory diseases [4]. Tregs inhibit the activation of both innate and adaptive immune cells via inhibitory surface molecules (like cytotoxic T-lymphocyte antigen-4 (CTLA-4) and lymphocyte-activation gene-3) and secretion of immunosuppressive cytokines (interleukin (IL)-10, transforming growth factor-β and IL-35). Both Treg subsets are equally important to prevent inflammation-induced tissue damage during acute infections and to promote tissue repair, which is particularly shown in the influenza infection model [4, 5].

PD-L1 dictates the balance between Treg and IFN-γ responses induced by α-(1,3)-glucan. Our data provide a rationale for the exploitation of immunotherapeutic approaches that target PD-1-PD-L1 to enhance protective immune responses to A. fumigatus infections.

Basophils are a rare granulocyte population that has been associated with allergic and inflammatory responses. It is essential to understand the regulatory mechanisms by which basophils are kept in check, considering the impact of dysregulated basophil function on immune responses under different pathological conditions. Among immunoregulatory cells, CD4CD25FoxP3 regulatory T cells (T) are the key players that maintain immune tolerance. The mechanisms by which T regulate and suppress diverse immune cell subsets have been studied extensively, but the impact of T on basophil functions is not well understood. We report that human basophils are refractory to T-mediated suppression and found that T stimulate resting basophils to induce the expression of activation markers including CD69, CD203c, and CD13 and the release of basophil cytokines including IL-13, IL-8, and IL-4. Mechanistically, T could induce human basophil activation via IL-3 and STAT5 activation, whereas cellular contact was dispensable. Inhibition of either IL-3-IL-3 receptor interactions or STAT5 phosphorylation abrogated T-mediated activation of basophils. These results provide evidence of direct positive effects that human T have on basophil activation and reveal a previously unrecognized feature of this cell subset well known for immunosuppressive functions.

Foamy macrophages (FM)s harbor lipid bodies that not only assist mycobacterial persistence within the granulomas but also are sites for intracellular signaling and inflammatory mediators which are essential for mycobacterial pathogenesis. However, molecular mechanisms that regulate intracellular lipid accumulation in FMs during mycobacterial infection are not clear. Here, we report for the first time that jumonji domain containing protein (JMJD)3, a demethylase of the repressive H3K27me3 mark, orchestrates the expression of M. tuberculosis H37Rv-, MDR-JAL2287-, H37Ra- and M. bovis BCG-induced genes essential for FM generation in a TLR2-dependent manner. Further, NOTCH1-responsive RNA-binding protein MUSASHI (MSI), targets a transcriptional repressor of JMJD3, Msx2-interacting nuclear target protein, to positively regulate infection-induced JMJD3 expression, FM generation and M2 phenotype. Investigations in in vivo murine models further substantiated these observations. Together, our study has attributed novel roles for JMJD3 and its regulators during mycobacterial infection that assist FM generation and fine-tune associated host immunity.

No Activation Activation Intravenous immunoglobulin (IVIG) activates human basophils through direct interaction with surface-bound IgE, and by IL-3-and Syk-dependent mechanisms Background: Therapeutic normal IgG or intravenous immunoglobulin (IVIG) exerts anti-inflammatory effects through several mutually nonexclusive mechanisms. Recent data in mouse models of autoimmune disease suggest that IVIG induces IL-4 in basophils by enhancing IL-33 in SIGN-related 1-positive innate cells. However, translational insight on these data is lacking. Objective: We sought to investigate the effect of IVIG on human basophil functions. Methods: Isolated circulating basophils from healthy donors were cultured in the presence of IL-3, IL-33, GM-CSF, thymic stromal lymphopoietin, or IL-25. The effect of IVIG and F(ab') 2 and Fc IVIG fragments was examined based on expression of

Autophagy plays an important role in the regulation of autoimmune and autoinflammatory responses of the immune cells. Defective autophagy process is associated with various autoimmune and inflammatory diseases. Moreover, in many of these diseases, the therapeutic use of normal immunoglobulin G or intravenous immunoglobulin (IVIG), a pooled normal IgG preparation, is well documented. Therefore, we explored if IVIG immunotherapy exerts therapeutic benefits via induction of autophagy in the immune cells. Here we show that IVIG induces autophagy in peripheral blood mononuclear cells (PBMCs). Further dissection of this process revealed that IVIG-induced autophagy is restricted to inflammatory cells like monocytes, dendritic cells, and M1 macrophages but not in cells associated with Th2 immune response like M2 macrophages. IVIG induces autophagy by activating AMP-dependent protein kinase, beclin-1, class III phosphoinositide 3-kinase and p38 mitogen-activated protein kinase and by inhibiting mammalian target of rapamycin. Mechanistically, IVIG-induced autophagy is F(ab′) 2-dependent but sialylation independent, and requires endocytosis of IgG by innate cells. Inhibition of autophagy compromised the ability of IVIG to suppress the inflammatory cytokines in innate immune cells. Moreover, IVIG therapy in inflammatory myopathies such as dermatomyositis, antisynthetase syndrome and immune-mediated necrotizing myopathy induced autophagy in PBMCs and reduced inflammatory cytokines in the circulation, thus validating the translational importance of these results. Our data provide insight on how circulating normal immunoglobulins maintain immune homeostasis and explain in part the mechanism by which IVIG therapy benefits patients with autoimmune and inflammatory diseases.

Interaction between innate immune cells and parasite plays a key role in the immunopathogenesis of lymphatic filariasis. Despite being professional antigen presenting cells critical for the pathogen recognition, processing and presenting the antigens for mounting T cell responses, the dendritic cell response and its role in initiating CD4 + T cell response to filaria, in particular Wuchereria bancrofti , the most prevalent microfilaria is still not clear. Herein, we demonstrate that a 70 kDa phosphorylcholine-binding W. bancrofti sheath antigen induces human dendritic cell maturation and secretion of several pro-inflammatory cytokines. Further, microfilarial sheath antigen-stimulated dendritic cells drive predominantly Th1 and regulatory T cell responses while Th17 and Th2 responses are marginal. Mechanistically, sheath antigen-induced dendritic cell maturation, and Th1 and regulatory T cell responses are mediated via toll-like receptor 4 signaling. Our data suggest that W. bancrofti sheath antigen exploits dendritic cells to mediate distinct CD4 + T cell responses and immunopathogenesis of lymphatic filariasis.

The programed death-1 (PD-1)–programed death ligand-1 (PD-L1) and PD-L2 co-inhibitory pathway has been implicated in the evasion strategies of Mycobacterium tuberculosis. Specifically, M. tuberculosis-induced PD-L1 orchestrates expansion of regulatory T cells and suppression of Th1 response. However, the role of PD pathway in regulating Th17 response to M. tuberculosis has not been investigated. In the present report, we demonstrate that M. tuberculosis and M. tuberculosis-derived antigen fractions have differential abilities to mediate human monocyte- and dendritic cell (DC)-mediated Th17 response and were independent of expression of PD-L1 or PD-L2 on aforementioned antigen-presenting cells. Importantly, we observed that blockade of PD-L1 or PD-1 did not significantly modify either the frequencies of Th17 cells or the production of IL-17 from CD4+ T cells though IFN-γ response was significantly enhanced. On the contrary, IL-1β from monocytes and DCs were critical for the Th17 response to M. tuberculosis. Together, our results indicate that IL-1β, but not members of the programed death pathway, is critical for human Th17 response to M. tuberculosis.