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A New Mechanism for Inhalational Priming: IL-4 Bypasses Innate Immune Signals¹

Department for Immunobiology, Yale School of Medicine, New Haven, CT 06520

Signaling via innate immune mechanisms is considered pivotal for T cell-mediated responses to inhaled Ags. Furthermore, Th2 cells specific for one inhaled Ag can facilitate priming of naive T cells to unrelated new inhaled Ags, a process we call "Th2 collateral priming". Interestingly, our previous studies showed that collateral priming is independent of signals via the innate immune system but depends on IL-4 secretion by CD4⁺ T cells. We thus hypothesized that IL-4 can bypass the need for signals via the innate immune system, considered essential for pulmonary priming. Indeed, we were able to show that IL-4 bypasses the requirement for TLR4- and MyD88-mediated signaling for responses to new allergens. Furthermore, we characterized the mechanisms by which IL-4 primes for new inhaled allergens: "IL-4-dependent pulmonary priming" relies on IL-4 receptor expression on hematopoietic cells and structural cells. Transfer experiments indicate that within the hematopoietic compartment both T cells and dendritic cells need to express the IL-4 receptor. Finally, we were able to show that IL-4 induces recruitment and maturation of myeloid dendritic cells in vivo and increases T cell recruitment to the draining lymph nodes. Our findings bring new mechanistic knowledge to the phenomenon of polysensitization and primary sensitization in asthma.

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 This work was supported by grants from the Philip Morris External Research Program "Influence of Lung Inflammation on Th2 Priming" (to K.B.), the National Institutes of Health Grant R01 HL54450-09 (to K.B.), and the Deutsche Forschungsgemeinschaft (DI 1224/1-1 to A.M.D.).

² Current address: Junior Research Group Leader, Collaborative Research Center 587, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.

³ Current address: President’s Office, Wellesley College, 106 Central Street, Wellesley, MA 02481.

⁴ Address correspondence and reprint requests to Dr. Anna M. Dittrich, Junior Research Group Leader, Collaborative Research Center 587, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail address: dittrich.anna-maria{at}mh-hannover.de

⁵ Abbreviations used in this paper: IL-4R, -chain of the IL-4 receptor; BAL, bronchoalveolar lavage; BALF, BAL fluid; BM, bone marrow; BMDC, BM-derived dendritic cell; LN, lymph node; mLN, mediastinal LN; TLR4d, mouse strain defective in signaling via TLR4; WT, wild type; KO, knockout.