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Plasmacytoid Dendritic Cells Cross-Prime Naive CD8 T Cells by Transferring Antigen to Conventional Dendritic Cells Through Exosomes

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Plasmacytoid Dendritic Cells Cross-Prime Naive CD8 T Cells by Transferring Antigen to Conventional Dendritic Cells Through Exosomes Plasmacytoid dendritic cells cross-prime naive CD8 T cells by transferring antigen to conventional dendritic cells through exosomes Chunmei Fua, Peng Pengb, Jakob Loschkoc, Li Fengb, Phuong Phamb, Weiguo Cuid, Kelvin P. Leeb, Anne B. Kruge, and Aimin Jianga,1 aCenter for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202; bDepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263; cII Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; dBlood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53213; and eInstitute for Immunology, Biomedical Center, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany Edited by Peter Cresswell, Yale University, New Haven, CT, and approved August 11, 2020 (received for review February 6, 2020) Although plasmacytoid dendritic cells (pDCs) have been shown to in human cancers, indicating pDC-mediated anti-tumor immunity play a critical role in generating viral immunity and promoting (14, 18–22). However, how pDCs function in generating CD8 tolerance to suppress antitumor immunity, whether and how pDCs T cell immunity remains poorly understood. cross-prime CD8 T cells in vivo remain controversial. Using a pDC- Although initially thought of as the less efficient antigen pre- targeted vaccine model to deliver antigens specifically to pDCs, we senting cells (APCs), pDCs can present antigens to activate both have demonstrated that pDC-targeted vaccination led to strong CD4 T cells as well as CD8 T cells through cross-presentation cross-priming and durable CD8 T cell immunity. Surprisingly, cross- (23, 24). Cross-priming, the activation of naive CD8 T cells fol- presenting pDCs required conventional DCs (cDCs) to achieve cross- lowing DC-mediated cross-presentation—the process through priming in vivo by transferring antigens to cDCs. Taking advantage which exogenous antigens are processed and presented onto of an in vitro system where only pDCs had access to antigens, we MHC class I molecules—plays a major role in generating CD8 further demonstrated that cross-presenting pDCs were unable to T cell immunity against cancers and viruses, upon vaccination, as efficiently prime CD8 T cells by themselves, but conferred antigen- well as in the induction of immune tolerance (cross-tolerance) IMMUNOLOGY AND INFLAMMATION naive cDCs the capability of cross-priming CD8 T cells by transferring (25–28). Recent discovery that type 1 cDCs (cDC1s) cross- antigens to cDCs. Although both cDC1s and cDC2s exhibited similar primed antigen-specific CD8 T cells in tumors has highlighted efficiency in acquiring antigens from pDCs, cDC1s but not cDC2s the importance of DC-mediated cross-priming in generating were required for cross-priming upon pDC-targeted vaccination, CD8 T cell immunity and in determining the efficacy of cancer suggesting that cDC1s played a critical role in pDC-mediated cross- immunotherapies, including immune checkpoint blockade (ICB) priming independent of their function in antigen presentation. An- (29–32). However, the function and roles of pDCs in cross- tigen transfer from pDCs to cDCs was mediated by previously un- priming have remained understudied and not well understood. reported pDC-derived exosomes (pDCexos), that were also In fact, despite pDCs having been shown to be capable of cross- produced by pDCs under various conditions. Importantly, all these presentation in vitro (33–37), even the involvement of pDCs in pDCexos primed naive antigen-specific CD8 T cells only in the pres- cross-priming in vivo is still under debate (26, 38–40). Several ence of bystander cDCs, similarly to cross-presenting pDCs, thus studies have suggested that pDCs were either not involved in or identifying pDCexo-mediated antigen transfer to cDCs as a mecha- nism for pDCs to achieve cross-priming. In summary, our data sug- gest that pDCs employ a unique mechanism of pDCexo-mediated Significance antigen transfer to cDCs for cross-priming. Whether and how pDCs cross-prime CD8 T cells in vivo remain plasmacytoid dendritic cells | conventional dendritic cells | antigen controversial despite extensive studies. Using a vaccine model transfer | exosomes | cross-priming where antigens were only delivered to pDCs, this report dem- onstrated that pDCs induced cross-priming and durable CD8 T cell immunity in vivo. However, cross-presenting pDCs re- s the initiators of antigen-specific immune responses, den- quired cDCs to achieve cross-priming by transferring antigens to dritic cells (DCs) play a central role in regulating both T cell A cDCs. cDC1s but not cDC2s played a critical role in pDC-mediated immunity and tolerance (1). There are two major DC pop- cross-priming, despite both subsets acquiring antigens from ulations, conventional/classical DCs (cDCs) and the plasmacy- pDCs similarly. Antigen transfer from pDCs to bystander cDCs toid DCs (pDCs). While both cDCs and pDCs could be was mediated by pDC-derived exosomes (pDCexos), which were developed from a common DC progenitor (CDP) and share key generated under various conditions. Importantly, these pDCexos transcriptional factors and dependence on Fms-like tyrosine ki- required cDCs to prime CD8 T cells, similarly to cross-presenting nase 3 ligand (Flt3-L), pDCs were most noted as a unique DC pDCs, thus identifying the pDCexo/cDCs pathway as a mecha- subset that produced large amount of type I interferons (IFN-I) nism for pDCs to achieve cross-priming. and have been extensively studied for their function in generat- ing antiviral immunity by sensing viral RNA and DNA by toll- Author contributions: C.F., P. Peng, and A.J. designed research; C.F., P. Peng, L.F., P. Pham, like receptor (TLR)-7 and -9 (2–10). Besides their function in and A.J. performed research; J.L., W.C., K.P.L., and A.B.K. contributed new reagents/ producing IFN-I, recent studies have also highlighted that pDCs analytic tools; C.F. and A.J. analyzed data; and C.F. and A.J. wrote the paper. exert strong tolerogenic functions to mediate immune tolerance The authors declare no competing interest. by inducing T cell deletion, CD4 T cell anergy, and Treg dif- This article is a PNAS Direct Submission. ferentiation (4, 11, 12). In tumors, pDCs are generally thought to Published under the PNAS license. play a tolerogenic role, as accumulation of pDCs in multiple tu- 1To whom correspondence may be addressed. Email: [email protected]. mors was often associated with poor prognosis (4, 6, 13–17). On This article contains supporting information online at https://www.pnas.org/lookup/suppl/ the other hand, activation of pDCs has also been reported to in- doi:10.1073/pnas.2002345117/-/DCSupplemental. duce immunogenic responses and has shown therapeutic efficacy www.pnas.org/cgi/doi/10.1073/pnas.2002345117 PNAS Latest Articles | 1of12 Downloaded by guest on September 25, 2021 incapable of cross-priming in vivo. For example, pDCs did not cDCs in vivo, leading to presentation of antigens on MHCII for at cross-present viral antigens during either influenza A virus (IAV) least 72 h (71, 72). As immunization with anti-Siglec-H-Ag have or herpes simplex virus 1 (HSV-1) infection (41, 42), and de- been shown to prime CD4 T cell to mediate tolerance either with pletion of pDCs did not affect cross-presentation and clearance or without adjuvant (71), we decided to first use pDC-targeting of viral antigens (43). CpG-stimulated pDCs have been shown to anti-Siglec-H-OVA to examine whether pDCs cross-prime CD8 be defective in cross-priming naive CD8 T cells compared to cDCs T cells in vivo, and if so whether pDC-mediated cross-priming (44), and pDCs were not able to cross-prime naive CD8 T cells similarly leads to CD8 T cell tolerance. Wild-type (WT) mice in vivo (45). On the other hand, other reports have suggested that were immunized with anti-Siglec-H-OVA either with or without pDCs did cross-prime CD8 T cells in vivo (46–49). Despite the TLR9 agonist CpG following adoptive transfer of 5- (6)-carboxy- controversy, however, it’s likely that pDCs at least play some roles fluorescein diacetate succinimidyl diester (CFSE)-labeled OVA- in regulating cross-priming, as increasing evidence has emerged specific CD8 T (OTI) cells, lymph node (LN) and spleen cells showing that both pDCs and cDCs are required to achieve optimal were then examined for CD8 T cell responses. Immunization with cross-priming and CD8 T cell immunity under diverse conditions anti-Siglec-H-OVA alone led to some proliferation of OTI cells in (50–55). Furthermore, immunotherapies with pDCs either alone both LN and spleen (Fig. 1 A and B). However, the addition of or in combination with cDCs have shown promising clinical results CpG greatly enhanced the proliferation of transferred OTI cells, (18, 21, 22, 56, 57), although it remains unclear whether pDCs resulting in about a three- to fourfold increase in the percentages exert their effects directly through their cross-priming or indirectly of Thy1.1+ OTI cells in spleen and LN, respectively (Fig. 1A). by regulating other immune cells (i.e., cDCs, T cells, and natural Examination of CFSE dilution further revealed that immunization killer [NK] cells) through pDC activation and subsequent pro- with anti-Siglec-H-OVA plus CpG resulted in about 80% of duction of IFN-I and other cytokines (58, 59). Thus, there is a Thy1.1 OTI T cells that have undergone more than five cycles of critical need to better understand whether and how pDCs cross- proliferation, compared to 30 to 40% with anti-Siglec-H-OVA prime CD8 T cells to advance these promising pDC-based im- alone (Fig. 1B). Thus, while the OVA antigen was cross-presented munotherapies clinically. to CD8 T cells by anti-Siglec-H-OVA alone, addition of an ad- Exosomes are small membrane vesicles about 30- to 150-nm juvant CpG substantially improved efficacy of antigen cross- diameter in sizes that form within late multivesicular endosomal presentation.
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