Activation and Regulation of B Cell Responses by Invariant Natural Killer T Cells.

CD1d-restricted invariant natural killer T (iNKT) cells play central roles in the activation and regulation of innate and adaptive immunity. Cytokine-mediated and CD1d-dependent interactions between iNKT cells and myeloid and lymphoid cells enable iNKT cells to contribute to the activation of multiple cell types, with important impacts on host immunity to infection and tumors and on the prevention of autoimmunity. Here, we review the mechanisms by which iNKT cells contribute to B cell maturation, antibody and cytokine production, and antigen presentation. Cognate interactions with B cells contribute to the rapid production of antibodies directed against conserved non-protein antigens resulting in rapid but short-lived innate humoral immunity. iNKT cells can also provide non-cognate help for the generation of antibodies directed against protein antigens, by promoting the activation of follicular helper T cells, resulting in long-lasting adaptive humoral immunity and B cell memory. iNKT cells can also regulate humoral immunity by promoting the development of autoreactive B cells into regulatory B cells. Depletions and functional impairments of iNKT cells are found in patients with infectious, autoimmune and malignant diseases associated with altered B cell function and in murine models of these conditions. The adjuvant and regulatory activities that iNKT cells have for B cells makes them attractive therapeutic targets for these diseases.

CD4+ T cells require either B cells or CD8+ T cells to control spread and pathogenesis of a neurotropic infection.

Immunity within the brain, specifically to virus-infected neurons, must be controlled to prevent neuron loss and impairment, though the process by which this occurs remains unclear. Here, we use a mouse model of neuron-restricted measles virus infection, in which immunocompetent adults survive challenge, whereas T and B cell-deficient mice succumb. This model allowed us to more precisely define the contributions of CD4+ T cells, CD8+ T cells, and B cells in neuroprotection. Both B cell knockout mice and mice depleted of CD8+ T cells survive challenge and show no signs of illness, though are less able to control viral replication than immunocompetent mice. In contrast, depletion of CD4+ T cells results in disease and death in all infected mice, though the kinetics of illness are delayed compared to RAG knockout mice. Our data suggest a coordinated interplay of adaptive immune components, which collectively controls viral spread and limits neuropathogenesis.

Get It through Your Thick Head: Emerging Principles in Neuroimmunology and Neurovirology Redefine Central Nervous System "Immune Privilege".

The central nervous system (CNS) coordinates all aspects of life, autonomic and sentient, though how it has evolved to contend with pathogenic infections remains, to a great degree, a mystery. The skull and cerebrospinal fluid (CSF) provide protection from blunt force contacts, and it was once thought that the blood-brain barrier (BBB) was a fortress that restricted pathogen entry and limited inflammation. Recent studies, however, have caused a revision of this viewpoint: the CNS is monitored by blood-borne lymphocytes, but can use alternative strategies to prevent or resolve many pathogenic challenges. In this Review, we discuss emerging principles that indicate how the CNS is immunologically unique from peripheral tissues. We focus on developments that include glymphatics, recently characterized brain lymphatic vessels, distinctions in innate and adaptive immune strategies, novel points of entry for neurotropic viruses, and, finally, how the periphery can influence CNS homeostasis and immune responses within the brain. Collectively, these attributes demand a re-evaluation of immunity in the brain: not privileged, but distinct.

Extended JAK activation and delayed STAT1 dephosphorylation contribute to the distinct signaling profile of CNS neurons exposed to interferon-gamma.

Although interferon-gamma (IFN-γ) plays a critical role in the noncytolytic elimination of many neurotropic viral infections, the signaling response to this cytokine has not been extensively characterized in primary CNS neurons. We previously demonstrated that the IFN-γ response at the signaling and gene expression levels is temporally extended in primary mouse hippocampal neurons, as compared to the transient response of primary mouse embryonic fibroblasts (MEF). We hypothesize that the protracted kinetics of STAT1 phosphorylation in IFN-γ-treated neurons are due to extended receptor activation and/or delayed STAT1 dephosphorylation in the nucleus. Here, we show that in response to IFN-γ, the Janus kinases (JAK1/JAK2) associated with the neuronal IFN-γ receptor complex remain active for an extended period as compared to MEF. Experimental inactivation of JAK1/JAK2 in neurons after IFN-γ treatment did not reverse the extended STAT1 phosphorylation phenotype. These results suggest that the extended kinetics of neuronal IFN-γ signaling are a product of distinct negative feedback mechanisms operating at both the receptor and within the nucleus.