Strikingly, DCs from BALB/c mice cocultured with CD83-deficient CD4+ conventional T cells showed enhanced CD40 expression and IL-12 secretion compared with DCs cocultured with CD4+ conventional T cells from CD83flox/flox/CD4-crewt/wt wild-type mice. In summary, these results indicate that endogenous CD83 expression in CD4+ conventional T cells plays a crucial role in controlling CD4+ T cell responses, at least in part, by regulating the activity of CD11c+ DCs. Copyright © 2020 by The American Association of Immunologists, Inc.Naive CD8+ T cell survival in the periphery is critically dependent on tonic TCR signaling through peptide + MHC class I (MHCI) recognition; however, little is known about how natural variation in MHCI levels impacts the naive CD8+ T cell repertoire. Using mice that are hemizygous or homozygous for a single MHCI allele, we showed that despite a reduction in peripheral CD8+ T cell numbers of ∼50% in MHCI hemizygous mice, MHCI levels had no notable impact on the rate of thymic generation or emigration of CD8 single-positive T cells. Moreover, the peripheral T cell repertoire in hemizygous mice showed selective retention of T cell clonotypes with a greater competitive advantage as evidenced by increased expression of CD5 and IL-7Rα. The qualitative superiority of CD8+ T cells retained in hemizygous mice was also seen during influenza A virus infection, in which epitope-specific CD8+ T cells from hemizygous mice had a higher avidity for pMHCI and increased cytokine polyfunctionality, despite a reduced response magnitude. Collectively, this study suggests that natural variation in MHCI expression levels has a notable and biologically relevant impact on the maintenance, but not generation, of the naive CD8+ T cell repertoire. Copyright © 2020 by The American Association of Immunologists, Inc.B lymphocytes are important players of the adaptive immune system. However, not just activation of B cells but also regulation of B cell signaling is important to prevent hyperactivity and dysregulation of the immune response. Different mechanisms and proteins contribute to this balance. One of these is CD22, a member of the Siglec family. It is an inhibitory coreceptor of the BCR and inhibits B cell activation. Upon BCR stimulation, CD22-dependent inhibition of BCR signaling results in a decreased calcium mobilization. Although some CD22 binding partners have already been identified, the knowledge about the CD22 interactome is still incomplete. In this study, quantitative affinity purification-mass spectrometry enabled the delineation of the CD22 interactome in the B cell line DT40. These data will clarify molecular mechanisms and CD22 signaling events after BCR activation and revealed several new CD22-associated proteins. One new identified interaction partner is the E3 ubiquitin ligase cullin 3, which was revealed to regulate CD22 surface expression and clathrin-dependent CD22 internalization after BCR stimulation. Furthermore cullin 3 was identified to be important for B lymphocytes in general. B cell-specific cullin 3-deficient mice show reduced developing B cells in the bone marrow and a severe pro-B cell proliferation defect. Mature B cells in the periphery are also reduced and characterized by increased CD22 expression and additionally by preactivated and apoptotic phenotypes. The findings reveal novel functions of cullin 3 in B lymphocytes, namely regulating CD22 surface expression and internalization after B cell activation, as well as promoting proliferation of pro-B cells. Copyright © 2020 by The American Association of Immunologists, Inc.Radiation therapy is capable of directing adaptive immune responses against tumors by stimulating the release of endogenous adjuvants and tumor-associated Ags. Within the tumor, conventional type 1 dendritic cells (cDC1s) are uniquely positioned to respond to these signals, uptake exogenous tumor Ags, and migrate to the tumor draining lymph node to initiate cross-priming of tumor-reactive cytotoxic CD8+ T cells. In this study, we report that radiation therapy promotes the activation of intratumoral cDC1s in radioimmunogenic murine tumors, and this process fails to occur in poorly radioimmunogenic murine tumors. In poorly radioimmunogenic tumors, the adjuvant polyinosinic-polycytidylic acid overcomes this failure following radiation and successfully drives intratumoral cDC1 maturation, ultimately resulting in durable tumor cures. Depletion studies revealed that both cDC1 and CD8+ T cells are required for tumor regression following combination therapy. We further demonstrate that treatment with radiation and polyinosinic-polycytidylic acid significantly expands the proportion of proliferating CD8+ T cells in the tumor with enhanced cytolytic potential and requires T cell migration from lymph nodes for therapeutic efficacy. Thus, we conclude that lack of endogenous adjuvant release or active suppression following radiation therapy may limit its efficacy in poorly radioimmunogenic tumors, and coadministration of exogenous adjuvants that promote cDC1 maturation and migration can overcome this limitation to improve tumor control following radiation therapy. BGJ398 solubility dmso Copyright © 2020 by The American Association of Immunologists, Inc.Secreted phospholipase A2 (sPLA2) enzymes release free fatty acids, including arachidonic acid, and generate lysophospholipids from phospholipids, including membrane phospholipids from cells and bacteria and surfactant phospholipids. We have shown that an endogenous enzyme sPLA2 group X (sPLA2-X) is elevated in the airways of asthmatics and that mice lacking the sPLA2-X gene (Pla2g10) display attenuated airway hyperresponsiveness, innate and adaptive immune responses, and type 2 cytokine production in a model of airway sensitization and challenge using a complete allergen that induces endogenous adjuvant activity. This complete allergen also induces the expression of sPLA2-X/Pla2g10 In the periphery, an sPLA2 found in bee venom (bee venom PLA2) administered with the incomplete Ag OVA leads to an Ag-specific immune response. In this study, we demonstrate that both bee venom PLA2 and murine sPLA2-X have adjuvant activity, leading to a type 2 immune response in the lung with features of airway hyperresponsiveness and Ag-specific type 2 airway inflammation following peripheral sensitization and subsequent airway challenge with OVA.