T(H)17 cells mediate pulmonary collateral priming.

BACKGROUND: Our laboratory has shown that inhalational sensitization to new antigens is facilitated through an ongoing T(H)2-polarized inflammation of the lung, a phenomenon we call "collateral priming." OBJECTIVE: We were interested to analyze whether a T(H)1-polarized pulmonary inflammation also facilitates priming toward new antigens and which cytokine or cytokines are involved. METHODS: T(H)1-polarized T cells were generated in vitro and transferred into congenic mice. Mice were challenged initially with cognate antigen and an unrelated antigen; consecutively, they received cognate antigen or the secondary antigen. Airway inflammation, antigen-specific IgG2a levels, and airway hyperresponsiveness were assessed to determine the inflammatory phenotype, with antibody blocking studies used to determine cytokine requirements for T(H)1 collateral priming. RESULTS: Our experiments revealed that ongoing inflammation of the lung induced by the transfer of T(H)1-polarized cells also facilitates priming toward new antigens, which results in lymphocytic inflammation of the lung. Interestingly, blocking studies identified IL-17A as a major contributor to this pathology. Accordingly, we could demonstrate for the first time that T(H)17-polarized cells alone can facilitate priming toward new antigens, inducing lymphocytic airway inflammation and strong airway hyperresponsiveness. Flow cytometric analysis revealed priming of endogenous T cells for IL-17A secretion with a distinct memory/effector phenotype compared to T(H)1 cells, thus presenting an exciting model to further elucidate differentiation of T(H)17 cells. CONCLUSIONS: We show that airway inflammation mediated by T(H)17 cells facilitates sensitization to new antigens and confers increased airway responsiveness in a murine model of polysensitization, suggesting a mechanism involving IL-17A behind the increased risk for allergic sensitization in polysensitized subjects.

TLR4 signaling in stromal cells is critical for the initiation of allergic Th2 responses to inhaled antigen.

Allergic asthma is an inflammatory lung disease driven by Th2. We have shown that both Th1 and Th2 sensitization to inhaled OVA depend on the presence and concentration of LPS, where high concentrations (LPS(hi)) induce Th1 and low concentrations (LPS(lo)), Th2. Stromal cells (SCs), such as airway SCs, exacerbate established airway disease; however, little is known about their role early during sensitization. In this study, using bone marrow chimeric mice to restrict TLR4 signaling to either the SC compartment (SC(+)HPC(-)) or the hematopoietic cell (HPC) compartment (SC(-)HPC(+)), we report that HPC TLR4 is necessary and sufficient for Th1 sensitization to OVA-LPS(hi), whereas TLR4 in both compartments is required for Th2 sensitization to OVA-LPS(lo). Surprisingly, although SC(+)HPC(-) mice were unable to generate a Th1 response to OVA-LPS(hi), they instead mounted a robust Th2 response, indicating that in the presence of higher concentrations of LPS, SC TLR4 is sufficient for Th2 sensitization. We show that the SC TLR4 response to LPS leads to induction of Th2-inducing dendritic cells that upregulate Notch ligand Jagged-1 but not Delta-4. Furthermore, airway SCs upregulate thymic stromal lymphopoietin in response to exposure to both OVA-LPS(lo) and OVA-LPS(hi). These studies demonstrate that SC TLR4 signaling is critically involved in Th2 but not Th1 sensitization to inhaled Ag.

A new mechanism for inhalational priming: IL-4 bypasses innate immune signals.

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.