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Trogocytosis of Peptide–MHC Class II Complexes from Dendritic Cells Confers Antigen-Presenting Ability on Basophils

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Trogocytosis of Peptide–MHC Class II Complexes from Dendritic Cells Confers Antigen-Presenting Ability on Basophils Trogocytosis of peptide–MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils Kensuke Miyakea, Nozomu Shiozawaa, Toshihisa Nagaoa, Soichiro Yoshikawaa, Yoshinori Yamanishia, and Hajime Karasuyamaa,1 aDepartment of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved December 7, 2016 (received for review September 26, 2016) Th2 immunity plays important roles in both protective and allergic function as antigen-presenting cells (APCs) and induce Th2 dif- responses. Nevertheless, the nature of antigen-presenting cells ferentiation in cooperation with basophil-derived IL-4. responsible for Th2 cell differentiation remains ill-defined com- Reports from three independent groups further expanded the pared with the nature of the cells responsible for Th1 and Th17 cell role for basophils in Th2 differentiation and demonstrated in differentiation. Basophils have attracted attention as a producer of three distinct experimental settings that basophils, rather than Th2-inducing cytokine IL-4, whereas their MHC class II (MHC-II) DCs, are the critical APCs for driving Th2 differentiation (5–7). expression and function as antigen-presenting cells are matters of In all settings, basophils expressed both MHC class II (MHC-II) considerable controversy. Here we revisited the MHC-II expression and costimulatory molecules (CD80, CD86, or CD40) necessary for on basophils and explored its functional relevance in Th2 cell APC function, and could process and present antigens. Depletion differentiation. Basophils generated in vitro from bone marrow of basophils but not DCs abolished Th2 differentiation in vivo. This cells in culture with IL-3 plus GM-CSF displayed MHC-II on the cell paradigm shift was greeted with great enthusiasm, but also with surface, whereas those generated in culture with IL-3 alone did not. criticism (16, 18, 19). One concern is the method used for the Of note, these MHC-II–expressing basophils showed little or no tran- depletion of DCs and basophils, pointing out the possibility that scription of the corresponding MHC-II gene. The GM-CSF addition to radioresistant DCs may have remained intact in the DC-depleted INFLAMMATION culture expanded dendritic cells (DCs) other than basophils. Cocul- chimeric mice (20) and that the basophil-depleting anti-FceRI an- IMMUNOLOGY AND ture of basophils and DCs revealed that basophils acquired peptide– tibody may have ablated FceRI-expressing inflammatory DCs (21). MHC-II complexes from DCs via cell contact-dependent trogocytosis. Indeed, the crucial role of DCs in Th2 differentiation was dem- The acquired complexes, together with CD86, enabled basophils to onstrated by later studies (20–23). Of note, basophils reportedly stimulate peptide-specific T cells, leading to their proliferation and express H-2M and invariant chain, which are key regulators of IL-4 production, indicating that basophils can function as antigen- peptide loading on MHC-II, at very low levels compared with DCs, presenting cells for Th2 cell differentiation. Transfer of MHC-II from raising concerns about the basophil’s antigen-processing and pre- DCs to basophils was also detected in draining lymph nodes of mice sentation ability (21). Moreover, the level of MHC-II expression on with atopic dermatitis-like skin inflammation. Thus, the present basophils varies, depending on experimental conditions, but it is study defined the mechanism by which basophils display MHC-II generally much lower than that on professional APCs such as DCs on the cell surface and appears to reconcile some discrepancies ob- and B cells (5–8). Thus, the significance of MHC-II expression on served in previous studies. basophils and the antigen-presentation capacity of basophils remain controversial (24). basophil | dendritic cell | MHC class II | trogocytosis In the present study, we revisited MHC-II expression on baso- phils and examined it in various cytokine milieus. Unexpectedly, asophils, the rarest granulocytes, have long been considered Berroneously as minor relatives or blood-circulating precur- Significance sors of tissue-resident mast cells because of phenotypic similarity between them, including basophilic granules in the cytoplasm and Recent studies have revealed that basophils, the rarest granulocytes, the expression of high-affinity IgE receptor FceRI on the cell have crucial roles in various immune responses. Among their surface (1). However, recent studies have revealed that basophils properties, the MHC class II (MHC-II) expression and their and mast cells play distinct roles in immune responses such as al- function as antigen-presenting cells are matters of considerable lergic inflammation and protective immunity to parasitic infections controversy. Here we show that basophils indeed express MHC-II – on the cell surface, but with little transcription of corresponding (2 4). Basophils also contribute to immune regulation through – – genes. This could be achieved by the acquisition of peptide MHC-II their interaction with other types of cells, including T cells (5 8), complexes from dendritic cells via cell contact-dependent trogo- monocytes (9, 10), innate lymphoid cells (11), fibroblasts (12, 13), cytosis in vitro and in vivo. The acquired complexes enabled ba- and endothelial cells (14). sophils to stimulate and differentiateTcellstowardTh2cells.Thus, Basophils rapidly secrete larger quantities of IL-4 than Th2 cells the present study clarified the mechanism by which basophils on a per cell basis in response to a variety of stimuli (15). IL-4 has display MHC-II on the cell surface and appears to reconcile some an important role in promoting the differentiation of naive T cells discrepancies observed in previous studies. to Th2 cells (16). Sokol et al. demonstrated that basophils tran- siently migrate to draining lymph nodes just before Th2 differen- Author contributions: K.M., S.Y., Y.Y., and H.K. designed research; K.M., N.S., and T.N. performed research; S.Y. contributed new reagents/analytic tools; K.M. analyzed data; tiation occurs there, in response to subcutaneous injection of protease and K.M. and H.K. wrote the paper. allergenssuchaspapain(17).TheyarelocalizedintheT-cellzone The authors declare no conflict of interest. and express IL-4, and their depletion abolished Th2 differentia- This article is a PNAS Direct Submission. tion in lymph nodes (17). These results suggested that basophils 1To whom correspondence should be addressed. Email: [email protected]. are a crucial provider of IL-4 necessary for Th2 differentiation. In This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. this setting, it was originally assumed that dendritic cells (DCs) 1073/pnas.1615973114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1615973114 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 MHC-II expression was detected on cultured basophils at protein, Intriguingly, the GM-CSF addition induced little or no transcrip- but not at transcription level. We here demonstrate that baso- tional up-regulation of the H2Ab1 gene encoding MHC-II pro- phils acquired peptide–MHC-II complexes from DCs through cell teins in BMBAs (Fig. 1D), despite the increased level of MHC-II contact-dependent trogocytosis in vitro and in vivo. Peptide– proteins on their surface (Fig. 1C). This was also the case for the MHC-II–dressed basophils could function as APCs and induced transcription of the Ciita gene, the master regulator of MHC-II the proliferation and IL-4 production of T cells. Thus, the present transcription (Fig. 1D). GM-CSF/IL-3-elicited BMBAs expressed study clarified the mechanism by which basophils display MHC-II the basophil-specific Mcpt8 gene, but not the DC-specific Zbtb46 on the cell surface and appears to reconcile some discrepancies gene (Fig. 1D), and possessed ring-like nuclei (Fig. S1B), as did observed in previous studies. authentic IL-3-elicited BMBAs. These results suggested that GM- CSF did not directly act on basophils to induce the transcription Results and translation of MHC-II and might influence the MHC-II ex- Basophils Express MHC-II at Protein but Not at Transcription Level. pression on basophils indirectly, via the effect on another type Basophils isolated from the bone marrow and spleen displayed of cells. MHC-II on their surface at very low levels, in contrast to high expression on professional APCs such as DCs and B cells (Fig. Basophils Acquire MHC-II Proteins from DCs. Flow cytometric anal- A ysis revealed that the addition of GM-CSF to the IL-3 culture of 1 ). Culture of basophils ex vivo with their survival and growth − + factor IL-3 did not up-regulate the MHC-II expression (Fig. 1B). bone marrow cells expanded the CD200R3 CD11c population The addition of other cytokines, including IFN-γ, thymic stromal (Fig. 2A). This population expressed high levels of GM-CSF re- lymphopoietin (TSLP), and GM-CSF, showed no significant effect ceptor and MHC-II (Fig. 2B), suggesting BMBAs might have ac- on it (Fig. 1B), even though IFN-γ is known to induce MHC-II quired MHC-II proteins from DCs in culture. To explore this expression on many types of cells (25). Considering that basophils possibility, we generated BMBAs from bone marrow cells of CD11cDTR mice, in that the diphtheria toxin receptor (DTR) is differentiate from their progenitor cells in the bone marrow, we + thought their MHC-II expression might be influenced by cytokine selectively expressed in CD11c cells. The treatment of their bone milieu during their differentiation, but not once they mature. Indeed, marrow cells in vitro with diphtheria toxin depleted most of + + C when bone marrow cells were cultured in the presence of IL-3 for 5 d CD11c MHC-II cells (Fig. 2 ; Fig. S2), and the culture of to generate bone marrow–derived basophils (BMBAs), the addition treated cells with IL-3 plus GM-CSF resulted in significant re- γ duction of MHC-II expression on BMBAs in comparison with the of GM-CSF, but not IFN- or TSLP, significantly up-regulated the + C expression in the presence of CD11c cells (Fig.
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