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T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is still fatal in many cases. T cell blasts are characterized by hyperactivation and strong proliferative and migratory capacities. The chemokine receptor CXCR4 is involved in mediating malignant T cell properties, and cortactin has been shown to control CXCR4 surface localization in T-ALL cells. We have previously shown that cortactin overexpression is correlated with organ infiltration and relapse in B-ALL. However, the role of cortactin in T cell biology and T-ALL remains elusive. Here, we analyzed the functional relevance of cortactin for T cell activation and migration and the implications for T-ALL development. We found that cortactin is upregulated in response to T cell receptor engagement and recruited to the immune synapse in normal T cells. Loss of cortactin caused reduced IL-2 production and proliferation. Cortactin-depleted T cells showed defects in immune synapse formation and migrated less due to impaired actin polymerization in response to T cell receptor and CXCR4 stimulation. Leukemic T cells expressed much higher levels of cortactin compared to normal T cells that correlated with greater migratory capacity. Xenotransplantation assays in NSG mice revealed that cortactin-depleted human leukemic T cells colonized the bone marrow significantly less and failed to infiltrate the central nervous system, suggesting that cortactin overexpression drives organ infiltration, which is a major complication of T-ALL relapse. Thus, cortactin could serve as a potential therapeutic target for T-ALL and other pathologies involving aberrant T cell responses.

Hyperinflammation present in individuals with severe COVID-19 has been associated with an exacerbated cytokine production and hyperactivated immune cells. Endoplasmic reticulum stress leading to the unfolded protein response has been recently reported as an active player in inducing inflammatory responses. Once unfolded protein response is activated, GRP78, an endoplasmic reticulum–resident chaperone, is translocated to the cell surface (sGRP78), where it is considered a cell stress marker; however, its presence has not been evaluated in immune cells during disease. Here we assessed the presence of sGRP78 on different cell subsets in blood samples from severe or convalescent COVID-19 patients. The frequency of CD45+sGRP78+ cells was higher in patients with the disease compared to convalescent patients. The latter showed similar frequencies to healthy controls. In patients with COVID-19, the lymphoid compartment showed the highest presence of sGRP78+ cells versus the myeloid compartment. CCL2, TNF-α, C-reactive protein, and international normalized ratio measurements showed a positive correlation with the frequency of CD45+sGRP78+ cells. Finally, gene expression microarray data showed that activated T and B cells increased the expression of GRP78, and peripheral blood mononuclear cells from healthy donors acquired sGRP78 upon activation with ionomycin and PMA. Thus, our data highlight the association of sGRP78 on immune cells in patients with severe COVID-19.

The quality of life in patients with inflammatory bowel diseases (IBD) is strongly impaired. Alterations of intestinal epithelial homeostasis contribute to the development and establishment of IBD. Intestinal Paneth and Paneth-like cells produce and secrete luminal proteins sustaining epithelial homeostasis. Here we show that IFN-γ stimulates Paneth and Paneth-like cells degranulation that triggers the proliferation of intestinal epithelial cells (IEC) in a Wnt/β-catenin independent manner. Degranulation in Paneth and Paneth-like cells was mTORC1 and necroptosis dependent. Remarkably, lack of IFN-γ, inhibition of mTORC1, or impeding necroptosis reduces IEC proliferation cytokine-mediated. Our findings identify a new role for IFN-γ in stimulating IEC proliferation through inducing degranulation of Paneth and Paneth-like cells which is mTORC1 and necroptosis- dependent. In a mouse model of colitis, mTORC1 activation and necroptosis regulate Paneth and Paneth-like cell secretion. Furthermore, the colitogenic environment triggers PC metaplasia in the distal region of the large intestine to simulate cell proliferation.Highlights:IFN-γ stimulates proliferation,β-catenin independent.IFN-γ enhances mitochondrial activity and proliferationIFN-γ regulates PC biogenesis.mTORC1-dependent necroptosis mediates secretion in Paneth and Paneth-like cells.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is still fatal in many cases. T cell blasts are characterized by hyperactivation and strong proliferative and migratory capacities. The chemokine receptor CXCR4 is involved in mediating malignant T cell properties and cortactin has been shown to control CXCR4 surface localization in T-ALL cells. We have previously shown that cortactin overexpression is correlated with organ infiltration and relapse in B-ALL. However, the role of cortactin in T cell biology and T-ALL remains elusive. Here, we analyzed the functional relevance of cortactin for T cell activation and migration and the implications for T-ALL development. We found that cortactin is upregulated in response to TCR engagement and recruited to the immune synapse in normal T cells. Loss of cortactin caused reduced IL-2 production and proliferation. Cortactin-depleted T cells showed defects in immune synapse formation and migrated less due to impaired actin polymerization in response to TCR and CXCR4 stimulation. Leukemic T cells expressed much higher levels of cortactin compared to normal T cells that correlated with greater migratory capacity. Xenotransplantation assays in NSG mice revealed that cortactin-depleted human leukemic T cells colonized the bone marrow significantly less and failed to infiltrate the central nervous system suggesting that cortactin overexpression drives organ infiltration, which is a major complication of T-ALL relapse. Thus, cortactin could serve as a potential therapeutic target for T-ALL and other pathologies involving aberrant T cell responses.

Immunological mechanisms of non-IgE-mediated cow's milk protein allergy (CMPA) are not well understood. Such a circumstance requires attention with the aim of discovering new biomarkers that could lead to better diagnostic assays for early treatment. Here, we sought both to investigate the mechanism that underlies non-IgE-mediated CMPA and to identify cow's milk immunoreactive proteins in a Mexican pediatric patient group (n = 34). Hence, we determined the IgE and IgG

The interleukin (IL)-1 superfamily of cytokines comprises 11 pro- and anti-inflammatory cytokines, which play essential roles during the immune response. Several pathogenic pathways are initiated by IL-1RL2 (interleukin 1 receptor-like 2) signaling, also known as IL-36R, in the skin, lungs, and gut. IL-36 cytokines promote the secretion of proinflammatory cytokines and chemokines, upregulation of antimicrobial peptides, proliferation mediators, and adhesion molecules on endothelial cells. In addition, the IL-36-IL-1RL2 axis has an essential role against viral infections, including a potential role in COVID-19 pathology. The evidence presented in this review highlights the importance of the axis IL-36-IL-1RL2 in the development of several inflammation-related diseases and the healing process. It suggests that IL-1RL2 ligands have specific roles depending on the tissue or cell source. However, there is still much to discover about this cytokine family, their functions in other organs, and how they accomplish a dual effect in inflammation and healing.