Qi Yang

SUMMARY: Mucosal IgA is critical for controlling the microbiota and preventing pathogenic infection of the epithelium. The innate signals that regulate the generation of IgA remain poorly defined. Here, we identified TRIF and IL-1R1 as immune checkpoints for intestinal IgA production. In the absence of infection, Trif ^−/− and Il1r1 ^−/− mice exhibited markedly elevated stool IgA and IgA-bound commensals. We show that IL-1R1 restricts IgA class-switching in a B cell-intrinsic manner, while TRIF acts extrinsically of B cells and shapes the Peyer’s patch microenvironment. Loss of either Trif or Il1r1 enhanced retinoic acid metabolism and allowed premature Ccnd3 upregulation in naive B cells, favoring both IgA class-switching and differentiation into germinal center B cells. During oral vaccination, the absence or blockade of the TRIF/IL-1R1 pathway increased antigen-specific IgA production without affecting seric antigen-specific IgG levels. These findings unveil novel and local signaling targets to promote robust antigen-specific mucosal immunity.

Background: Aging is known to induce the emergence of distinct lymphocyte populations with unique molecular and functional characteristics. However, the impact of aging on the transcriptomes and functional activities of CD4 and CD8 T cells in non-lymphoid tissue remains poorly understood. Investigating aging-induced transcriptomic changes in tissue-infiltrating immune cells may provide insights into tissue homeostasis and malignancy in the aging context.Methods: Single-cell RNA sequencing (scRNA-seq) was performed to compare the cell subsets and transcriptomes of CD4⁺ and CD8⁺ T cells in brain-associated tissue, including the meninges and choroid plexus of young and aged mice. Flow cytometry was used to analyze aging-associated CD4⁺ T cells in the hippocampus. Depletion antibodies were employed to investigate the functional role of aging-associated T cells.Results: Aging induces a shift in the transcriptomes of CD4⁺ and CD8⁺ T cells in the meninges and choroid plexus toward an effector memory phenotype. In aged mice, T helper 2 (Th2) cells, regulatory T cells (Tregs), and distinct subsets of CD153-expressing CD4⁺ T cells accumulate in these brain-associated regions. Notably, CD153-expressing CD4⁺ T cells also infiltrate the hippocampus. Depletion of CD153⁺ cells using anti-CD153 antibodies leads to impaired cognitive function, suggesting a potential protective role for these cells in the aging brain.Conclusions: Aging alters the transcriptome of brain-associated CD4⁺ and CD8⁺ T cells. In particular, distinct CD153-expressing CD4⁺ T cells accumulate in the meninges and choroid plexus, and also infiltrate the hippocampus during aging. These cells may play a protective role in maintaining brain homeostasis.

The role of immune cells in neurodegeneration remains incompletely understood. Accumulation of misfolded tau proteins is a hallmark of neurodegenerative diseases. Our recent study revealed the presence of mucosal-associated invariant T (MAIT) cells in the meninges, where they express antioxidant molecules to maintain meningeal barrier integrity. However, the role of MAIT cells in tau-related neuroinflammation and neurodegeneration remains unknown. Flow cytometry analysis was performed to examine MAIT cells in human Tau P301S transgenic mice. Tau pathology, hippocampus atrophy, meningeal integrity, and microglial gene expression were examined in Mr1^-/- P301S mice that lacked MAIT cells and control P301S transgenic mice, as well as Mr1^-/- P301S mice with adoptive transfer of MAIT cells. The meninges of P301S mutant human tau transgenic mice had increased numbers of MAIT cells, which retained their expression of antioxidant molecules. Mr1^-/-P301S mice that lacked MAIT cells exhibited increased tau pathology and hippocampus atrophy compared to control Mr1^+/+P301S mice. Adoptive transfer of MAIT cells reduced tau pathology and hippocampus atrophy in Mr1^-/- P301S mice. Meningeal barrier integrity was compromised in Mr1^-/-P301S mice, but not in control Mr1^+/+P301S mice. A distinctive microglia subset with a proinflammatory gene expression profile (M-inflammatory) was enriched in the hippocampus of Mr1^-/-P301S mice. The transcriptomes of the remaining microglia in these mice also shifted towards a proinflammatory state, with increased expression of inflammatory cytokines, chemokines, and genes related to ribosome biogenesis and immune responses to toxic substances. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation in the Mr1^-/- P301S mice. Our data indicate an important role for MAIT cells in regulating tau-pathology-related neuroinflammation and neurodegeneration.

Background: Idiopathic pulmonary fibrosis (IPF) is characterised by significant but poorly understood immune and antibody responses. This study examines the spatial transcriptomes and microenvironmental niches of antibody-producing plasma cells and tertiary lymphoid structures in IPF lungs, and the molecular pathways influencing antibody accumulation and pulmonary fibrosis.Methods: Explant lung tissues from IPF patients and control normal lungs were used for spatial transcriptome assays and validating RNAscope and immunofluorescence assays. Fibroblasts derived from IPF and control lungs were examined for their ability to attract plasma cells. Neutralising antibodies were administered to investigate molecules affecting pulmonary plasma cell accumulation and fibrosis in bleomycin-treated mice.Results: Human IPF lungs exhibited a remarkably widespread distribution of plasma cells and local antibodies in the fibrotic regions, disseminating from plasma cell-generating tertiary lymphoid structures. Novel mural cells wrapped the vessels in tertiary lymphoid structure regions, expressing C-C motif chemokine receptor 7 (CCR7) ligands that attracted T-cells into tertiary lymphoid structures to promote plasma cell generation. Distinct IPF-associated fibroblasts further secreted C-X-C motif chemokine ligand 12 (CXCL12), providing an extramedullary niche to foster the dissemination and accumulation of plasma cells in the fibrotic regions. Neutralisation of CCR7 ligands or CXCL12 reduced plasma cell and local antibody accumulation in the lungs of bleomycin-treated mice, leading to reduced transforming growth factor β concentrations and alleviated pulmonary fibrosis.Conclusions: Plasma cells and local antibodies are widely distributed in the fibrotic regions of IPF lungs. Distinct subsets of IPF-associated mural cells and fibroblasts promote pathological plasma cell and antibody accumulation. These findings have potential implications for strategies aimed at targeting immune and antibody responses to combat IPF.

The role of immune cells in neurodegeneration remains incompletely understood. Our recent study revealed the presence of mucosal-associated invariant T (MAIT) cells in the meninges, where they express antioxidant molecules to maintain meningeal barrier integrity. Accumulation of misfolded tau proteins are a hallmark of neurodegenerative diseases. The role of MAIT cells in tau-related neuroinflammation and neurodegeneration, however, remains unclear. Here we report that the meninges of P301 mutant human tau transgenic mice had increased numbers of MAIT cells, which retained their expression of antioxidant molecules. Mr1 ^−/− P301S mice that lacked MAIT cells exhibited increased tau pathology and hippocampus atrophy compared to control Mr1 ^+/+ P301S mice. Adoptive transfer of MAIT cells reduced tau pathology and hippocampus atrophy in Mr1 ^−/− P301S mice. Meningeal barrier integrity was compromised in Mr/ ^−/− P301S mice, but not in control Mr1 ^+/+ P301S mice. A distinctive microglia subset with proinflammatory gene expression profile (M-inflammatory) was enriched in the hippocampus of Mr1 ^−/− P301S mice. The transcriptomes of the remaining microglia in these mice also shifted towards a proinflammatory state, with increased expression of inflammatory cytokines, chemokines, and genes related with ribosome biogenesis and immune responses to toxic substances. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation in the Mr1 ^−/− P301S mice. Together, our data indicate an important role for MAIT cells in regulating tau-pathology-related neuroinflammation and neurodegeneration.

Increasing evidence indicates close interaction between immune cells and the brain, revising the traditional view of the immune privilege of the brain. However, the specific mechanisms by which immune cells promote normal neural function are not entirely understood. Mucosal-associated invariant T cells (MAIT cells) are a unique type of innate-like T cell with molecular and functional properties that remain to be better characterized. In the present study, we report that MAIT cells are present in the meninges and express high levels of antioxidant molecules. MAIT cell deficiency in mice results in the accumulation of reactive oxidative species in the meninges, leading to reduced expression of junctional protein and meningeal barrier leakage. The presence of MAIT cells restricts neuroinflammation in the brain and preserves learning and memory. Together, our work reveals a new functional role for MAIT cells in the meninges and suggests that meningeal immune cells can help maintain normal neural function by preserving meningeal barrier homeostasis and integrity.

The interaction between the immune system and the nervous system remains an intriguing enigma. Recent studies indicate that innate lymphoid cells (ILCs), a unique family of innate effector cells, participate in intense cross talk with the nervous system. In the mucosal barrier sites, ILCs have been found to co-localize with neurons, nerves, glial cell projectors, and neuroendocrine cells. The cross talk between ILCs and peripheral nervous system orchestrates mucosal homeostasis and immunity. In addition, the barrier tissues of the central nervous system (CNS) also provide conductive microenvironment for ILC development and maintenance. Activities of CNS-associated ILCs impact the outcome of various CNS disorders. In this chapter, we review and discuss the intricate and bidirectional interaction between ILCs and nervous system. Keywords Innate lymphoid cells Neuroimmunology The enteric nervous system Meningeal immunity Choroid plexus

Aging is paradoxically associated with a deteriorated immune defense (immunosenescence) and increased basal levels of tissue inflammation (inflammaging). The lung is particularly sensitive to the effects of aging. The immune cell mechanisms underlying physiological lung aging remain poorly understood. Here we reveal that aging leads to increased interferon signaling and elevated concentrations of chemokines in the lung, which is associated with infiltration of monocytes into the lung parenchyma. scRNA‐seq identified a novel Type‐1 interferon signaling dependent monocyte subset (MO‐ifn) that upregulated IFNAR1 expression and exhibited greater transcriptomal changes with aging than the other monocytes. Blockade of type‐1 interferon signaling by treatment with anti‐IFNAR1 neutralizing antibodies rapidly ablated MO‐ifn cells. Treatment with anti‐IFNAR1 antibodies also reduced airway chemokine concentrations and repressed the accumulation of the overall monocyte population in the parenchyma of the aged lung. Together, our work suggests that physiological aging is associated with increased basal level of airway monocyte infiltration and inflammation in part due to elevated type‐1 interferon signaling.