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

Abstract

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.

Pneumocystis Infection in an Immunocompetent Host Can Promote Collateral Sensitization to Respiratory Antigens

“…Furthermore, when mice were given an intranasal application of ovalbumin (ova) during this peak inflammatory response, they developed sensitization to ova, in the form of airway hyperresponsiveness upon later antigen challenge, without the requirement of previous extrapulmonary sensitization. This sensitization proved to be dependent on interleukin-4 (IL-4) signaling, which has previously been described to be a hallmark of collateral sensitization (10). We also found that the degree of exposure to the exogenous antigen (ova) required to cause sensitization was less during a Pneumocystis infection than what has been reported for other early respiratory infections, such as those caused by RSV (45).…”

“…More recent studies have characterized a more general model in which inhalational sensitization occurs in the lung during an ongoing inflammation (10). Because this sensitization can occur to antigens unrelated to the original infection or inflammation, the authors have termed this "collateral sensitization."…”

Spatial regulation of IL-4 signalling in vivo

“…Our data demonstrated that bystander cells exposed to ambient IL-4 signalling in a Th2 active lymph node became functionally biased, such that their response to a subsequent, antigen-specific stimulus resulted in unexpected Th2 polarisation [66]. A similar phenomenon has been observed during allergic asthma and was described as 'collateral priming' [70,71].…”

Essential Role of IL-4 and IL-4Rα Interaction in Adaptive Immunity of Zebrafish: Insight into the Origin of Th2-like Regulatory Mechanism in Ancient Vertebrates

“…Likewise, the time point used around 72 h also had been reported in other animal models, including mammals. For example, in vivo treatment with recombinant IL-4 for 72 h directly increased dendritic cell (DC) maturation and T cell recruitment independent of innate immune signals in a mouse model (63). According to these observations, it could be considered that the function of IL-4 is a critical driver in the priming and initiation of Th2-type adaptive immunity and is crucial for the recruitment, maturation, and activation of DCs and T lymphocytes by upregulating a number of key regulatory factors, such as CD40, CD154, CD80/86, CD83, and DC-SIGN/CD209.…”