Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms ...underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells. This surveillance is enabled by endothelial and mural cells forming the sinus stromal niche. T cell recognition of CSF-derived antigens at this site promoted tissue resident phenotypes and effector functions within the dural meninges. These findings highlight the critical role of dural sinuses as a neuroimmune interface, where brain antigens are surveyed under steady-state conditions, and shed light on age-related dysfunction and neuroinflammatory attack in animal models of multiple sclerosis.
Display omitted
•CNS-derived antigens accumulate at dural sinuses and are captured by dural APCs•Dural sinus-associated APCs present CSF-borne antigens to patrolling T cells•The dural sinus stroma orchestrates T cell trafficking•Immune hubs along dural sinuses allow CNS immunosurveillance
Rustenhoven et al. identify the dural sinuses as a neuroimmune interface, where patrolling T cells survey brain- and CSF-derived antigens to enable CNS immune surveillance. This niche is altered during aging and neuroinflammation and may represent a new therapeutic target for neurological diseases.
Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T ...cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.
Summary
Intestinal eosinophils are implicated in homeostatic and disease‐associated processes, yet the phenotype of intestinal tissue‐dwelling eosinophils is poorly defined and their roles in ...intestinal health or disease remain enigmatic. Here we probed the phenotype and localization of eosinophils constitutively homed to the small intestine of naive mice at baseline, and of antigen‐sensitized mice following intestinal challenge. Eosinophils homed to the intestinal lamina propria of naive mice were phenotypically distinguished from autologous blood eosinophils, and constitutively expressed antigen‐presenting cell markers, suggesting that intestinal eosinophils, unlike blood eosinophils, may be primed for antigen presentation. We further identified a previously unrecognized resident population of CD11chi eosinophils that are recovered with intraepithelial leucocytes, and that are phenotypically distinct from both lamina propria and blood eosinophils. To better visualize intestinal eosinophils in situ, we generated eosinophil reporter mice wherein green fluorescent protein expression is targeted to both granule‐delimiting and plasma membranes. Analyses of deconvolved fluorescent z‐section image stacks of intestinal tissue sections from eosinophil reporter mice revealed eosinophils within intestinal villi exhibited dendritic morphologies with cellular extensions that often contacted the basement membrane. Using an in vivo model of antigen acquisition in antigen‐sensitized mice, we demonstrate that both lamina propria‐associated and intraepithelium‐associated eosinophils encounter, and are competent to acquire, lumen‐derived antigen. Taken together these data provide new foundational insights into the organization and functional potential of intestinal tissue‐dwelling eosinophils, including the recognition of different subsets of resident intestinal eosinophils, and constitutive expression of antigen‐presenting cell markers.
“Eosinophils are implicated in intestinal homeostasis and disease, yet the phenotype of intestinal tissue‐dwelling eosinophils is poorly defined and their roles in intestinal health or disease remain enigmatic. This study applies complementary flow cytometry and histopathological approaches in wild‐type and newly generated eosinophil reporter mice to investigate tissue‐resident eosinophils at baseline and after antigen sensitization and challenge. These data provide new foundational insights into the organization and functional potential of tissue‐dwelling eosinophils, including the recognition of different subsets of resident intestinal eosinophils, and constitutive expression of antigen‐presenting cell markers.”
Conventional type 1 dendritic cells (cDC1)
are thought to perform antigen cross-presentation, which is required to prime CD8
T cells
, whereas cDC2 are specialized for priming CD4
T cells
. CD4
T ...cells are also considered to help CD8
T cell responses through a variety of mechanisms
, including a process whereby CD4
T cells 'license' cDC1 for CD8
T cell priming
. However, this model has not been directly tested in vivo or in the setting of help-dependent tumour rejection. Here we generated an Xcr1
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 CD8
T cell priming required the expression of major histocompatibility class I molecules by cDC1. Unexpectedly, early priming of CD4
T cells against tumour-derived antigens also required cDC1, and this was not simply because they transport antigens to lymph nodes for processing by cDC2, as selective deletion of major histocompatibility class II molecules in cDC1 also prevented early CD4
T cell priming. Furthermore, deletion of either major histocompatibility class II or CD40 in cDC1 impaired tumour rejection, consistent with a role for cognate CD4
T cell interactions and CD40 signalling in cDC1 licensing. Finally, CD40 signalling 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 of the direct orchestration of their cross-talk that is required for optimal anti-tumour immunity.
Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses ...targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood-brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b(+) antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.
The importance of immunoproteasomes to antigen presentation has been unclear because animals totally lacking immunoproteasomes had not been available. Having now developed mice lacking the three ...immunoproteasome catalytic subunits, we found that the dendritic cells of these mice had defects in presenting several major histocompatibility complex (MHC) class I epitopes. During viral infection in vivo, the presentation of a majority of MHC class I epitopes was markedly reduced in immunoproteasome-deficient animals compared with wild-type animals, whereas presentation of MHC class II peptides was unaffected. According to mass spectrometry, the repertoire of MHC class I-presented peptides was ∼50% different from that in wild-type mice, and these differences were sufficient to stimulate robust transplant rejection of wild-type cells in mutant mice. These results indicated that immunoproteasomes were more important in antigen presentation than previously thought.
Chirality is ubiquitous in biological systems, which is closely related to biological functions, life processes, and even the pathogenesis of diseases. However, the interface between the chirality of ...synthetic materials and organisms, particularly the immune system, remains poorly understood. Here, supramolecular chiral polymer micelles (SCPMs) are prepared by complexing antigenic proteins with chiral amino acid‐modified polyethyleneimine. The introduction of chirality not only reduces the toxicity of cationic polymer, but also benefits cell uptake and antigen presentation. Especially, D‐chirality presents the lowest cytotoxicity, while promoting the highest expression level of costimulatory molecules on dendritic cells compared to L‐chirality and achirality. The superiority of D‐chirality to stimulate dendritic cell maturation is supported by immunization with D‐SCPMs, which achieves significant antigen‐specific proliferation of T cells in the spleen, lymph nodes, and tumor of mice. Chirality‐mediated antigen processing and presentation are demonstrated by D‐SCPMs self‐assembled from chiral alkaline histidine or neutral phenylalanine modified polyethyleneimine and tumor associated ovalbumin or severe acute respiratory syndrome coronavirus 2 spike 1 antigenic protein. Immunoactivation enabled by D‐chirality opens a window to prepare potent nanotherapeutics for disease prevention and treatment.
Chiral polymer micelles are prepared by complexing antigens with chiral amino acid modified polyethyleneimine. D‐chiral micelles present the lowest cytotoxicity while promoting the highest activation levels of dendritic cells and antigen‐specific cytotoxic T cells compared to those of L‐chiral and achiral micelles. Immunoactivation mediated by D‐chirality opens a window to prepare potent nanotherapeutics for disease prevention and treatment.
Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy
. However, the reason some tumours have high CD8 T cell ...infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.
Antigen-presenting cells (APCs) play an important role in virus infection control by bridging innate and adaptive immune responses. Macrophages and dendritic cells (DCs) possess various surface ...receptors to recognize/internalize antigens, and antibody binding can enhance pathogen-opsonizing uptake by these APCs via interaction of antibody fragment crystallizable (Fc) domains with Fc receptors, evoking profound pathogen control in certain settings. Here, we examined phagocytosis-enhancing potential of Fc domains directly oriented on a retroviral virion/virus-like particle (VLP) surface. We generated an expression vector coding a murine Fc fragment fused to the transmembrane region (TM) of a retroviral envelope protein, deriving expression of the Fc-TM fusion protein on the transfected cell surface and production of virions incorporating the chimeric Fc upon co-transfection. Incubation of Fc-displaying simian immunodeficiency virus (SIV) with murine J774 macrophages and bone marrow-derived DCs derived Fc receptor-dependent enhanced uptake, being visualized by imaging cytometry. Alternative preparation of a murine leukemia virus (MLV) backbone-based Fc-displaying VLP loading an influenza virus hemagglutinin (HA) antigen resulted in enhanced HA internalization by macrophages, stating antigen compatibility of the design. Results show that the Fc-TM fusion molecule can be displayed on certain viruses/VLPs and may be utilized as a molecular adjuvant to facilitate APC antigen uptake.
•Antibody Fc can be surface-displayed on virions and virus-like particles (VLPs).•Fc-displaying viruses/VLPs undergo enhanced uptake by antigen-presenting cells.•Imaging cytometry depicts enhanced Fc-displayed virus internalization.•Loading antigen-compatible design can harness immunization regimens.
Presentation of peptide antigens by MHC-II proteins is prerequisite to effective CD4 T cell tolerance to self and to recognition of foreign antigens. Antigen uptake and processing pathways as well as ...expression of the peptide exchange factors HLA-DM and HLA-DO differ among the various professional and non-professional antigen-presenting cells and are modulated by cell developmental state and activation. Recent studies have highlighted the importance of these cell-specific factors in controlling the source and breadth of peptides presented by MHC-II under different conditions. During inflammation, increased presentation of selected self-peptides has implications for maintenance of peripheral tolerance and autoimmunity.
PDF
