Key Points This study has identified a novel capture mechanism for host-derived vesicles within the spleen and lymph node. This pathway modulates the immune response to circulating particulate antigens.

Intact human pregnancy can be regarded as an immunological paradox in that the maternal immune system accepts the allogeneic embryo without general immunosuppression. Because dendritic cell (DC) subsets could be involved in peripheral tolerance, the uterine mucosa (decidua) was investigated for DC populations. Here we describe the detailed immunohistochemical and functional characterization of HLA-DR-positive antigen-presenting cells (APCs) in early pregnancy decidua. In contrast to classical macrophages and CD83(+) DCs, which were found in comparable numbers in decidua and nonpregnant endometrium, only decidua harbored a significant population of HLA-DR(+)/DC-SIGN(+) APCs further phenotyped as CD14(+)/CD4(+)/CD68(+/-)/CD83(-)/CD25(-). These cells exhibited a remarkable proliferation rate (9.2 to 9.8% of all CD209(+) cells) by double staining with Ki67 and proliferating cell nuclear antigen. Unique within the DC-family, the majority of DC-SIGN(+) decidual APCs were observed in situ to have intimate contact with CD56(+)/CD16(-)/ICAM-3(+) decidual natural killer cells, another pregnancy-restricted cell population. In vitro, freshly isolated CD14(+)/DC-SIGN(+) decidual cells efficiently took up antigen, but could not stimulate naive allogeneic T cells at all. Treatment with an inflammatory cytokine cocktail resulted in down-regulation of antigen uptake capacity and evolving capacity to effectively stimulate resting T cells. Fluorescence-activated cell sorting analysis confirmed the maturation of CD14(+)/DC-SIGN(+) decidual cells into CD25(+)/CD83(+) mature DCs. In summary, this is the first identification of a uterine immature DC population expressing DC-SIGN, that appears only in pregnancy-associated tissue, has a high proliferation rate, and a conspicuous association with a natural killer subset.

Costimulatory signals are required to achieve robust chimeric antigen receptor (CAR) T cell expansion, function, persistence and antitumor activity. These can be provided by incorporating intracellular signalling domains from one or more T cell costimulatory molecules, such as CD28 or 4‐1BB, into the CAR. The selection and positioning of costimulatory domains within a CAR construct influence CAR T cell function and fate, and clinical experience of autologous anti‐CD19 CAR T cell therapies suggests that costimulatory domains have differential impacts on CAR T cell kinetics, cytotoxic function and potentially safety profile. The clinical impacts of combining costimulatory domains and of alternative costimulatory domains are not yet clearly established, and may be construct‐ and disease‐specific. The aim of this review is to summarise the function and effect of established and emerging costimulatory domains and their combinations within CAR T cells.

Dendritic cells are professional antigen-presenting cells that initiate primary immunity. Migration from sites of antigen uptake to lymphoid organs is crucial for the generation of immune responses. We investigated the migratory pathways specifically of epidermal Langerhans cells by tracing them from the epidermis to the draining lymph nodes. This was possible with a new monoclonal antibody, directed against murine Langerin/CD207, a type II lectin specific for Langerhans cells. In situ, resident, and activated Langerhans cells express Langerin in the epidermis and on their way through dermal lymphatic vessels. Both emigrated and trypsinization-derived Langerhans cells expressed high levels of Langerin intracellularly but reduced it upon prolonged culture periods. Sizeable numbers of Langerin+ cells were found in skin draining lymph nodes but not in mesenteric nodes. Langerin+ cells localized to the T cells areas and rarely to B cell zones. Numbers of Langerin-expressing cells increased after application of a contact sensitizer. In the steady state, Langerhans cells in the skin-draining nodes expressed maturation markers, such as 2A1 and costimulatory molecules CD86 and CD40. These molecules, CD86 and CD40, were further upregulated upon inflammatory stimuli such as contact sensitization. Thus, the novel anti-Langerin monoclonal antibody permits the unequivocal visualization of migratory Langerhans cells in the lymph nodes for the first time and thereby allows to dissect the relative immunogenic or tolerogenic contributions of Langerhans cells and other types of dendritic cells.

The human uterus is generally considered to be an immunologically privileged site that isolates the implanted allogeneic embryo from an aggressive maternal immune response. This is in contrast to the fact that the decidua, like other mucosal surfaces, must be able to respond to different types of foreign antigens, including pathogenic organisms, seminal plasma, and fetal trophoblasts (FTBs). However, during hemochorial placentation, the direct contact between FTBs (which invade uterine mucosa, the decidua) and maternal immunocompetent cells in the decidua 1 suggests that mechanisms of tolerance must exist to avoid rejection of the conceptus.The human decidua is invested with a significant (up to 75% of all major histocompatibility complex (MHC) class I ϩ cells are CD45 ϩ ) and diverse population of leukocytes. 2,3 Nearly one fifth of decidual leukocytes are positive for MHC class II and are thought to be mostly macrophages. 4 The most abundant cell type of decidua are uterine-specific natural killer cells, the large granular lymphocytes (LGLs), 5 whereas T cells are sparse and B cells are virtually absent. 3,5 The decidual leukocyte population has been a center of interest for the understanding of the balance between maternal control of the extent of invasion of FTBs in the uterine wall 2-6 as well as acceptance of the allogeneic fetus in successful pregnancy.