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Alveolar Macrophages and Lung Dendritic Cells Sense RNA and Drive Mucosal IgA Responses

Juliana Bessa^*, Andrea Jegerlehner^*, Heather J. Hinton^*, Paul Pumpens, Philippe Saudan^*, Pascal Schneider and Martin F. Bachmann^1,*

^* Cytos Biotechnology AG, Zürich-Schlieren, Switzerland; Latvian Biomedical Research and Study Center, Riga, Latvia; and Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

The mechanisms regulating systemic and mucosal IgA responses in the respiratory tract are incompletely understood. Using virus-like particles loaded with single-stranded RNA as a ligand for TLR7, we found that systemic vs mucosal IgA responses in mice were differently regulated. Systemic IgA responses following s.c. immunization were T cell independent and did not require TACI or TGFβ, whereas mucosal IgA production was dependent on Th cells, TACI, and TGFβ. Strikingly, both responses required TLR7 signaling, but systemic IgA depended upon TLR7 signaling directly to B cells whereas mucosal IgA required TLR7 signaling to lung dendritic cells and alveolar macrophages. Our data show that IgA switching is controlled differently according to the cell type receiving TLR signals. This knowledge should facilitate the development of IgA-inducing vaccines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Martin F. Bachmann, Wagistrasse 25, 8952 Zürich-Schlieren, Switzerland. E-mail address: Martin.bachmann{at}cytos.com

² Abbreviations used in this paper: i.n., intranasal(ly); AFC, Ab-forming cell; APRIL, a proliferation-inducing ligand; BAFF, B cell-activating factor of the TNF family; BAL, bronchoalveolar lavage; BCMA, B cell maturation Ag; BM, bone marrow; CD40L, CD40 ligand; CSR, class switch recombination; DC, dendritic cell; DT, diphtheria toxin; DTR, DT receptor; iNOS, inducible NO synthase; LN, lymph node; MLN, mediastinal lymph node; NP, 4-hydroxy-3-nitrophenylacetate; TACI, transmembrane activator, calcium modulator, and cyclophilin ligand interactor; TD, T cell dependent; TI, T cell independent; VLP, virus-like particle; WT, wild type.