IFN-γ-producing T1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren's disease.

Sjögren's disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (T) cells occur in several autoimmune diseases, but their role in SjD is ambiguous.

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren's Syndrome.

Objectives: Sjögren's Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD.

Orai3 and Orai1 mediate CRAC channel function and metabolic reprogramming in B cells.

The essential role of store-operated Ca entry (SOCE) through Ca release-activated Ca (CRAC) channels in T cells is well established. In contrast, the contribution of individual Orai isoforms to SOCE and their downstream signaling functions in B cells are poorly understood. Here, we demonstrate changes in the expression of Orai isoforms in response to B cell activation.

Distinct roles of ORAI1 in T cell-mediated allergic airway inflammation and immunity to influenza A virus infection.

T cell activation and function depend on Ca signals mediated by store-operated Ca entry (SOCE) through Ca release-activated Ca (CRAC) channels formed by ORAI1 proteins. We here investigated how SOCE controls T cell function in pulmonary inflammation during a T helper 1 (T1) cell-mediated response to influenza A virus (IAV) infection and T2 cell-mediated allergic airway inflammation. T cell-specific deletion of did not exacerbate pulmonary inflammation and viral burdens following IAV infection but protected mice from house dust mite-induced allergic airway inflammation.

ORAI3 is dispensable for store-operated Ca2+ entry and immune responses by lymphocytes and macrophages.

Ca2+ signals regulate the function of many immune cells and promote immune responses to infection, cancer, and autoantigens. Ca2+ influx in immune cells is mediated by store-operated Ca2+ entry (SOCE) that results from the opening of Ca2+ release-activated Ca2+ (CRAC) channels. The CRAC channel is formed by three plasma membrane proteins, ORAI1, ORAI2, and ORAI3.

Cavβ1 regulates T cell expansion and apoptosis independently of voltage-gated Ca channel function.

TCR stimulation triggers Ca signals that are critical for T cell function and immunity. Several pore-forming α and auxiliary β subunits of voltage-gated Ca channels (VGCC) were reported in T cells, but their mechanism of activation remains elusive and their contribution to Ca signaling in T cells is controversial. We here identify Caβ1, encoded by Cacnb1, as a regulator of T cell function.

The volume-regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING-p53 signaling.

The volume-regulated anion channel (VRAC) is formed by LRRC8 proteins and is responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling. Besides chloride, VRAC transports other molecules, for example, immunomodulatory cyclic dinucleotides (CDNs) including 2'3'cGAMP. Here, we identify LRRC8C as a critical component of VRAC in T cells, where its deletion abolishes VRAC currents and RVD.

Novel Methods of Necroptosis Inhibition for Spinal Cord Injury Using Translational Research to Limit Secondary Injury and Enhance Endogenous Repair and Regeneration.

Spinal cord injuries (SCIs) pose an immense challenge from a clinical perspective as current treatments and interventions have been found to provide marginal improvements in clinical outcome (with varying degrees of success) particularly in areas of motor and autonomic function. In this review, the pathogenesis of SCI will be described, particularly as it relates to the necroptotic pathway which has been implicated in limiting recovery of SCI via its roles in neuronal cell death, glial scarring, inflammation, and axonal demyelination and degeneration. Major mediators of the necroptotic pathway including receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed-lineage kinase domainlike will be described in detail regarding their role in facilitating necroptosis.

Calcium regulation of T cell metabolism.

T cells are an essential component of the immune system that provide antigen-specific acute and long lasting immune responses to infections and tumors, ascertain the maintenance of immunological tolerance and, on the flipside, mediate autoimmunity in a variety of diseases. The activation of T cells through antigen recognition by the T cell receptor (TCR) results in transient and sustained Ca signals that are shaped by the opening of Ca channels in the plasma membrane and cellular organelles. The dynamic regulation of intracellular Ca concentrations controls a variety of T cell functions on the timescale of seconds to days after signal initiation.

To B, or not to B: Is calcium the answer?

B lymphocytes are an important component of the adaptive and innate immune system because of their ability to secrete antibodies and to present antigens to T cells, which is critical for immune responses to many pathogens. Abnormal B cell function is the cause of diseases including autoimmune, paraneoplastic, and immunodeficiency disorders. The development, survival, and function of B cells depend on signaling through the B cell receptor (BCR) and costimulatory receptors.

RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling.

Activating BRAF mutants and fusions signal as RAS-independent constitutively active dimers with the exception of BRAF V600 mutant alleles which can function as active monomers. Current RAF inhibitors are monomer selective, they potently inhibit BRAF V600 monomers but their inhibition of RAF dimers is limited by induction of negative cooperativity when bound to one site in the dimer. Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize.

Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead.

BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition.

ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers.