Calderon et al. define the origin, turnover, and functional characteristics of pancreatic macrophages at both the exocrine and endocrine sites under noninflammatory conditions.

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.

Summary Autoimmune diabetes is characterized by inflammatory infiltration; however the initiating events are poorly understood. We found that the islets of Langerhans in young non-obese diabetic (NOD) mice contained two antigen presenting cell (APC) populations: a major macrophage and a minor CD103+ dendritic cell (DC) population. By four weeks of age, CD4+ T cells entered islets coincident with an increase of CD103+ DCs. In order to examine the role of the CD103+ DCs in diabetes, we examined Batf3-deficient NOD mice that lacked the CD103+ DCs in islets and pancreatic lymph nodes. This led to a lack of autoreactive T cells in islets and, importantly, no incidence of diabetes. Additional examination revealed that presentation of major histocompatibility complex (MHC) class I epitopes in the pancreatic lymph nodes was absent with a partial impairment of MHC class II presentation. Altogether, this study reveals that CD103+ DCs were essential for autoimmune diabetes development.

Beta cells from nondiabetic mice transfer secretory vesicles to phagocytic cells. The passage was shown in culture studies where the transfer was probed with CD4 T cells reactive to insulin peptides. Two sets of vesicles were transferred, one containing insulin and another containing catabolites of insulin. The passage required live beta cells in a close cell contact interaction with the phagocytes. It was increased by high glucose concentration and required mobilization of intracellular Ca 2+ . Live images of beta cell-phagocyte interactions documented the intimacy of the membrane contact and the passage of the granules. The passage was found in beta cells isolated from islets of young nonobese diabetic (NOD) mice and nondiabetic mice as well as from nondiabetic humans. Ultrastructural analysis showed intraislet phagocytes containing vesicles having the distinct morphology of dense-core granules. These findings document a process whereby the contents of secretory granules become available to the immune system. autoimmune diabetes | autoimmunity | insulin reactivity | insulin-reactive T cells

SignificanceOur studies indicate that the resident macrophages of the pancreatic islets of Langerhans have a seminal role in the initiation and progression of autoimmune diabetes in NOD mice. In this study, islet macrophages were depleted by administration of a monoclonal antibody to the CSF-1 receptor. Macrophage depletion, either at the start of the autoimmune process or when diabetogenesis is active, leads to a significant reduction in diabetes incidence. Depletion of the islet macrophages reduces the entrance of T cells into islets and results in the absence of antigen presentation. Concordantly, a regulatory pathway develops that controls diabetes progression. We conclude that treatments that target the islet macrophages may have important clinical relevance for the control of autoimmune type 1 diabetes.

Ferris et al. show that macrophages in pancreatic islets express a gene signature of activation consistent with barrier macrophages. Macrophages are poised to react to blood inflammatory stimuli. In NOD mice, an additional immune activation signature is observed as early as 3 wk of age.

SignificanceHigh-affinity antibody responses involve selection of B cells in the germinal center (GC) by cognate interactions with T follicular helper (TFH) cells, which in turn must first be activated by classical dendritic cells (cDCs). We observe that Notch2-dependent cDC2s are required in vivo for induction of TFH cells, GC B cells, and specific antibody production in response to sheep red blood cell (SRBC) immunization. Notch2 signaling impacted a broad transcriptional program in cDC2s both at homeostasis and after SRBC immunization, although we have not identified a target gene that mediates TFH differentiation. Thus, Notch2 is a transcription factor that acts in cDCs and is selectively required for support of the GC reaction.

B cells are increasingly regarded as integral to the pathogenesis of multiple sclerosis (MS) in part due to the success of B cell depletion therapy. Multiple B cell-dependent mechanisms contributing to inflammatory demyelination of the central nervous system (CNS) have been explored using experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-dependent animal model for multiple sclerosis (MS). While B cell antigen presentation has been suggested to regulate CNS inflammation during EAE, direct evidence that B cells can independently support antigen-specific autoimmune responses by CD4 T cells in EAE is lacking. Using a newly developed murine model of in vivo conditional expression of MHCII, we previously reported that encephalitogenic CD4 T cells are incapable of inducing EAE when B cells are the sole antigen presenting cell. Herein we find that B cells cooperate with dendritic cells to enhance EAE severity resulting from myelin oligodendrocyte glycoprotein (MOG) immunization. Further, increasing the precursor frequency of MOG-specific B cells, but not addition of soluble MOG-specific antibody, is sufficient to drive EAE in mice expressing MHCII by B cells alone. These data support a model in which expansion of antigen-specific B cells during CNS autoimmunity amplifies cognate interactions between B and CD4 T cells and have the capacity to independently drive neuro-inflammation at later stages of disease.