Mutation of an L-type calcium channel gene leads to a novel primary cellular immunodeficiency in mice and humans

Human primary immunodeficiencies are inherited diseases that can provide valuable insight into our immune system. Calcium (Ca²⁺) is a vital secondary messenger in T cells that regulates a vast array of important events including maturation, homeostasis, activation, and apoptosis. The proper orchestration of Ca²⁺ signalling is essential to prevent immune related diseases. Upon antigen binding to the T cell receptor, extracellular Ca²⁺ enters the cell through CRAC, TRP and CaV channels. Here we describe a mutation in the L-type Ca²⁺ channel CaV1.4 leading to a novel immunological disorder. Three CaV1.4-deficient siblings presented with X-linked incomplete congenital stationary night blindness as well as recurrent infections, autoimmunity and pro-inflammatory cytokine production. The subjects uniformly exhibited a T cell memory phenotype and T cell exhaustion as well as chronic activation of their B cells. Moreover, their T cells but not B cells exhibited a reduced Ca²⁺ flux, compared to healthy control donors. This is the first example where the mutation of any CaV channel causes a primary immunodeficiency in humans and establishes their physiological importance in the immune system. In parallel, we detected a remarkably similar phenotype in a CaV1.4-deficient mouse model. In a separate set of experiments, a commercially available C57BL/6 mouse strain harbouring an undescribed mutation in Dock2, was introduced into our breeding stock resulting in some mice with a double deficiency of DOCK2 and CaV1.4. This provided the opportunity to assess the compound phenotype. We found that the double-deficient mouse model exhibited severe splenic cytopenia as well as chronic B cell activation but impaired BCR-induced activation / Ca²⁺ mobilization.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat

Type 2 Innate Lymphocytes Actuate Immunity Against Tumours and Limit Cancer Metastasis

Abstract Type 2 innate lymphoid cells (ILC2) potentiate immune responses, however, their role in mediating adaptive immunity in cancer has not been assessed. Here, we report that mice genetically lacking ILC2s have significantly increased tumour growth rates and conspicuously higher frequency of circulating tumour cells (CTCs) and resulting metastasis to distal organs. Our data support the model that IL-33 dependent tumour-infiltrating ILC2s are mobilized from the lungs and other tissues through chemoattraction to enter tumours, and subsequently mediate tumour immune-surveillance by cooperating with dendritic cells to promote adaptive cytolytic T cell responses. We conclude that ILC2s play a fundamental, yet hitherto undescribed role in enhancing anti-cancer immunity and controlling tumour metastasis

The role of the innate immune response regulatory gene ABCF1 in mammalian embryogenesis and development.

ABCF1 is an ABC transporter family protein that has been shown to regulate innate immune response and is a risk gene for autoimmune pancreatitis and arthritis. Unlike other members of ABC transporter family, ABCF1 lacks trans-membrane domains and is thought to function in translation initiation through an interaction with eukaryotic translation initiation factor 2 (eIF2). To study ABCF1 expression and function in development and disease, we used a single gene trap insertion in the Abcf1 gene in murine embryonic stem cells (ES cells) that allowed lineage tracing of the endogenous Abcf1 promoter by following the expression of a β-galactosidase reporter gene. From the ES cells, heterozygous mice (Abcf1+/-) were produced. No live born Abcf1-/- progeny were ever generated, and the lethality was not mouse strain-specific. Thus, we have determined that Abcf1 is an essential gene in development. Abcf1-/- mice were found to be embryonic lethal at 3.5 days post coitum (dpc), while Abcf1+/- mice appeared developmentally normal. Abcf1+/- mice were fertile and showed no significant differences in their anatomy when compared with their wild type littermates. The Abcf1 promoter was found to be active in all organs in adult mice, but varies in levels of expression in specific cell types within tissues. Furthermore, we observed high promoter activity in the blastocysts and embryos. Overall, Abcf1 expression in embryos is required for development and its expression in adults was highly correlated with actively proliferating and differentiating cell types