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.
Dittrich
Anna M
AM
Department for Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA. dittrich.anna-maria@mh-hannover.de
Chen
Hui-Chen
HC
Xu
Lan
L
Ranney
Patricia
P
Connolly
Sean
S
Yarovinsky
Timur O
TO
Bottomly
H Kim
HK
D000280:Administration, Inhalation; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D015847:Interleukin-4 / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011014:Pneumonia / Q000276:immunology*
D015847:Interleukin-4; D010047:Ovalbumin