Expression of XCR1 Characterizes the Batf3-Dependent Lineage of Dendritic Cells Capable of Antigen Cross-Presentation

143

148

Dendritic cells (DCs) consist of various subsets that play crucial roles in linking innate and adaptive immunity. In the murine spleen, CD8α+ DCs exhibit a propensity to ingest dying/dead cells, produce proinflammatory cytokines, and cross-present Ags to generate CD8+ T cell responses. To track and ablate CD8α+ DCs in vivo, we generated XCR1-venus and XCR1-DTRvenus mice, in which genes for a fluorescent protein, venus, and a fusion protein consisting of diphtheria toxin receptor and venus were knocked into the gene locus of a chemokine receptor, XCR1, which is highly expressed in CD8α+ DCs. In both mice, venus+ cells were detected in the majority of CD8α+ DCs, but they were not detected in any other cells, including splenic macrophages. Venus+CD8α+ DCs were superior to venus−CD8α+ DCs with regard to their cytokine-producing ability in response to TLR stimuli. In other tissues, venus+ cells were found primarily in lymph node (LN)-resident CD8α+, LN migratory and peripheral CD103+ DCs, which are closely related to splenic CD8α+ DCs, although some thymic CD8α−CD11b− and LN CD103−CD11b− DCs were also venus+. In response to dsRNAs, diphtheria toxin–treated XCR1-DTR mice showed impaired CD8+ T cell responses, with retained cytokine and augmented CD4+ T cell responses. Furthermore, Listeria monocytogenes infection and anti–L. monocytogenes CD8+ T cell responses were defective in diphtheria toxin–treated XCR1-DTRvenus mice. Thus, XCR1-expressing DCs were required for dsRNA- or bacteria-induced CD8+ T cell responses. XCR1-venus and XCR1-DTRvenus mice should be useful for elucidating the functions and behavior of XCR1-expressing DCs, including CD8α+ and CD103+ DCs, in lymphoid and peripheral tissues.

Section: Discussionsupporting

confidence: 81%

“…A chemokine receptor, XC chemokine receptor 1 (XCR1), is selectively expressed in splenic CD8a + and peripheral CD103 + DCs but is rare in other DC subsets or lymphocytes (26)(27)(28)(29)(30)(31). Human XCR1 expression is restricted to CD141 + DCs, which correspond to murine splenic CD8a + DCs (27-29, 32, 33).…”

mentioning

confidence: 99%

Critical Roles of a Dendritic Cell Subset Expressing a Chemokine Receptor, XCR1

Yamazaki

Sugiyama

Ohta

et al. 2013

143

148

“…+ CD24 low cells (6,7,27) showed that they were dominated by Ly-6C high monocytes and moDCs. In contrast, 24 h after laser microporation the numbers of LCs, XCR1…”

Section: Cd11bmentioning

confidence: 99%

Laser-Assisted Intradermal Delivery of Adjuvant-Free Vaccines Targeting XCR1+ Dendritic Cells Induces Potent Antitumoral Responses

Terhorst‐Molawi

Fossum

Barańska

et al. 2015

The development of vaccines inducing efficient CD8+ T cell responses is the focus of intense research. Dendritic cells (DCs) expressing the XCR1 chemokine receptor, also known as CD103+ or CD8α+ DCs, excel in the presentation of extracellular Ags to CD8+ T cells. Because of its high numbers of DCs, including XCR1+ DCs, the skin dermis is an attractive site for vaccine administration. By creating laser-generated micropores through the epidermis, we targeted a model protein Ag fused to XCL1, the ligand of XCR1, to dermal XCR1+ DCs and induced Ag-specific CD8+ and CD4+ T cell responses. Efficient immunization required the emigration of XCR1+ dermal DCs to draining lymph nodes and occurred irrespective of TLR signaling. Moreover, a single intradermal immunization protected mice against melanoma tumor growth in prophylactic and therapeutic settings, in the absence of exogenous adjuvant. The mild inflammatory milieu created in the dermis by skin laser microporation itself most likely favored the development of potent T cell responses in the absence of exogenous adjuvants. The existence of functionally equivalent XCR1+ dermal DCs in humans should permit the translation of laser-assisted intradermal delivery of a tumor-specific vaccine targeting XCR1+ DCs to human cancer immunotherapy. Moreover, considering that the use of adjuvants in vaccines is often associated with safety issues, the possibility of inducing protective responses against melanoma tumor growth independently of the administration of exogenous adjuvants should facilitate the development of safer vaccines.

“…Institutes of Health, Bethesda, MD), and anti-CD40 (FGK) by T. Rolink (University of Basel, Basel, Switzerland). Generation of anti-XCR1 mAb MARX10 (19) and anti-ICOS mAb (MIC-280 (25)) has been described before. The nonagonistic mAb MARX10 (mouse IgG2b, in the recombinant version IgG1) does not block the binding of XCL1 to XCR1.…”

Section: Expression and Purification Of Recombinant Proteinsmentioning

confidence: 99%

“…In the past few years, we and others recognized that the chemokine receptor XCR1 is exclusively expressed on the Batf3-dependent, crosspresenting DC and not elsewhere in the body (17)(18)(19). This highly restricted expression of XCR1 in the mouse is mirrored in the human system, where XCR1 can only be found on DC homologous to the mouse cross-presenting subset (18,20,21).…”

mentioning

confidence: 99%

Induction of Potent CD8 T Cell Cytotoxicity by Specific Targeting of Antigen to Cross-Presenting Dendritic Cells In Vivo via Murine or Human XCR1

Hartung

Becker

Bachem

et al. 2015

Self Cite

Current subunit vaccines are incapable of inducing Ag-specific CD8+ T cell cytotoxicity needed for the defense of certain infections and for therapy of neoplastic diseases. In experimental vaccines, cytotoxic responses can be elicited by targeting of Ag into cross-presenting dendritic cells (DC), but almost all available systems use target molecules also expressed on other cells and thus lack the desired specificity. In the present work, we induced CD8+ T cell cytotoxicity by targeting of Ag to XCR1, a chemokine receptor exclusively expressed on murine and human cross-presenting DC. Targeting of Ag with a mAb or the chemokine ligand XCL1 was highly specific, as determined with XCR1-deficient mice. When applied together with an adjuvant, both vector systems induced a potent cytotoxic response preventing the outgrowth of an inoculated aggressive tumor. By generating a transgenic mouse only expressing the human XCR1 on its cross-presenting DC, we could demonstrate that targeting of Ag using human XCL1 as vector is fully effective in vivo. The specificity and efficiency of XCR1-mediated Ag targeting to cross-presenting DC, combined with its lack of adverse effects, make this system a prime candidate for the development of therapeutic cytotoxic vaccines in humans.