A chronic demyelinating disease results from murine infection with the neurotropic strain JHM of mouse hepatitis virus (MHV-JHM). Demyelination is largely immune mediated. In this study, the individual roles of CD4 and CD8 T cells in MHV-induced demyelination were investigated using recombination-activating gene 1−/− (RAG1−/−) mice infected with an attenuated strain of MHV-JHM. These animals develop demyelination only after adoptive transfer of splenocytes from mice previously immunized to MHV. In this study, we show that, following adoptive transfer, virus-specific CD4 and CD8 T cells rapidly infiltrate the CNS of MHV-JHM-infected RAG1−/− mice. Adoptive transfer of CD4 T cell-enriched donors resulted in more severe clinical disease accompanied by less demyelination than was detected in the recipients of undepleted cells. Macrophage infiltration into the gray matter of CD4 T cell-enriched recipients was greater than that observed in mice receiving undepleted splenocytes. In contrast, CD8 T cell-enriched recipients developed delayed disease with extensive demyelination of the spinal cord. MHV-JHM-infected RAG1−/− mice receiving donors depleted of both CD4 and CD8 T cells did not develop demyelination. These results demonstrate that the development of demyelination following MHV infection may be initiated by either CD4 or CD8 T cells. Furthermore, they show that CD4 T cells contribute more prominently than CD8 T cells to the severity of clinical disease, and that this correlates with increased macrophage infiltration into the gray matter.

Evidence suggests that immunogenicity to mRNA-based SARS-CoV-2 vaccination in immunosuppressed patients may be reduced. This study assessed the response to 2 doses of mRNA-based SARS-CoV-2 vaccine among 133 participants with underlying chronic inflammatory disease, many of whom were receiving glucocorticoids, B-cell depletion therapy, or other immunosuppressant therapy.

The meninges contain adaptive immune cells that provide immunosurveillance of the CNS. These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial–meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells. which may help maintain immune privilege within the CNS.

Summary To understand lymphocyte behavior in the brain, 2-photon microscopy was used to visualize effector CD8+ T cells during toxoplasmic encephalitis. These cells displayed multiple behaviors with two distinct populations of cells apparent: one with a constrained pattern of migration versus a highly migratory subset. The proportion of these populations varied over time associated with changes in antigen availability as well as T cell expression of the inhibitory receptor PD1. Unexpectedly, the movement of infiltrating cells was closely associated with an infection-induced reticular system of fibers. This observation suggests that, whereas in other tissues there are pre-existing scaffolds that guide lymphocyte migration, in the brain specialized structures are induced by inflammation that guide migration of T cells in this immune-privileged environment.

Conventional type 1 dendritic cells (cDC1s 1 ) are thought to perform antigen cross-presentation required to prime CD8 T cells 2 , 3 , while cDC2 are considered specialized for priming CD4 T cells 4 , 5 . CD4 T cells are also thought to help CD8 T cell responses through a variety of mechanisms 6 – 11 , including a model in which CD4 T cells ‘license’ cDC1 for CD8 T cell priming 12 . However, this model has not been directly tested in vivo or in the setting of a help-dependent tumour rejection. Here, we generated an Xcr1 -Cre mouse strain to evaluate the cellular interactions that mediate tumour rejection in a model requiring CD4 and CD8 T cells. As expected, tumour rejection required cDC1, and expression of MHC-I by cDC1. Unexpectedly, early priming of CD4 T cell against tumour-derived antigens also required cDC1, which was not simply due to a role in antigen transport to lymph nodes for processing by cDC2, since selective deletion of MHC-II in cDC1 also prevented early CD4 T cell priming. Further, deletion of either MHC-II or CD40 in cDC1 impaired tumour rejection, consistent with a role for cognate CD4 T cell interactions and CD40 signaling in cDC1 licensing. Finally, CD40 signaling in cDC1 was critical not only for CD8 T cell priming, but also for initial CD4 T cell activation. Thus, in the setting of tumour-derived antigens, cDC1 function as an autonomous platform capable of antigen processing and priming for both CD4 and CD8 T cells and directly orchestrating their cross-talk required for optimal anti-tumour immunity.

Mice infected with mouse hepatitis virus strain JHM (MHV-JHM) develop a chronic demyelinating encephalomyelitis that is in large part immune mediated. Potential mechanisms of immune activity were assessed using an adoptive transfer system. Mice deficient in recombinase-activating gene function (RAG1−/−), defective in B- and T-cell maturation, become persistently infected with MHV but do not develop demyelination. Adoptive transfer of splenocytes from mice immunized to MHV into RAG1−/− mice infected with an attenuated strain of the virus results in the rapid and progressive development of demyelination. Most striking, adoptive transfer resulted, within 5 to 6 days, in extensive recruitment of activated macrophages/microglia to sites of demyelination within the spinal cord. Clearance of virus antigen occurred preferentially from the gray matter of the spinal cord. Apoptotic cells were identified in both the gray and white matter of the central nervous system (CNS) from RAG1−/− mice before and after adoptive transfer, with a moderate increase in number, but not distribution, of apoptotic cells following the development of demyelination. These results suggest that apoptosis following MHV-JHM infection of the murine CNS is not sufficient to cause demyelination. These results, showing that macrophage recruitment and myelin destruction occur rapidly after immune reconstitution of RAG−/− mice, suggest that this will be a useful system for investigating MHV-induced demyelination.

Background: Individuals with Chronic Inflammatory Diseases (CID) are frequently treated with immunosuppressive medications that can increase their risk of severe COVID-19. While novel mRNA-based SARS-CoV-2 vaccination platforms provide robust protection in immunocompetent individuals, the immunogenicity in CID patients on immunosuppression is not well established. Therefore, determining the potency of SARS-CoV-2 vaccines in the setting of immunosuppression is essential to risk-stratify CID patients with impaired protection and provide clinical guidance regarding medication management. Methods: We conducted a prospective assessment of mRNA-based vaccine immunogenicity in 133 adults with CIDs and 53 immunocompetent controls. Blood from participants over 18 years of age was collected before initial immunization and 1-2 weeks after the second immunization. Serum anti-SARS-CoV-2 spike (S) IgG+ binding, neutralizing antibody titers, and circulating S-specific plasmablasts were quantified to assess the magnitude and quality of the humoral response following vaccination. Results: Compared to immunocompetent controls, a three-fold reduction in anti-S IgG titers (P=0.009) and SARS-CoV-2 neutralization (p<0.0001) were observed in CID patients. B cell depletion and glucocorticoids exerted the strongest effect with a 36- and 10-fold reduction in humoral responses, respectively (p<0.0001). Janus kinase inhibitors and antimetabolites, including methotrexate, also blunted antibody titers in multivariate regression analysis (P<0.0001, P=0.0023, respectively). Other targeted therapies, such as TNF inhibitors, IL-12/23 inhibitors, and integrin inhibitors, had only modest impacts on antibody formation and neutralization. Conclusions: CID patients treated with immunosuppressive therapies exhibit impaired SARS-CoV-2 vaccine-induced immunity, with glucocorticoids and B cell depletion therapy more severely impeding optimal responses.

microRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS-model superoxide dismutase 1 (SOD1)(G93A) rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. To test miRNA inhibition in the central nervous system (CNS) as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the CNS and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1(G93A) mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS.