α‐galactosylceramide generates lung regulatory T cells through the activated natural killer T cells in mice

Abstract

Our previous study showed that intraperitoneal injection of α‐galactosylceramide (α‐GalCer) has the ability to activate lung iNKT cells, but α‐GalCer‐activated iNKT cells do not result in airway inflammation in wild‐type (WT) mice. Many studies showed that iNKT cells had the capacity to induce Treg cells, which gave rise to peripheral tolerance. Therefore, we examined the influence of intraperitoneal administration of α‐GalCer on the expansion and suppressive activity of lung Treg cells using iNKT cell‐knockout mice and co‐culture experiments in vitro. We also compared airway inflammation and airway hyperresponsiveness (AHR) after α‐GalCer administration in specific anti‐CD25 mAb‐treated mice. Our data showed that intraperitoneal injection of α‐GalCer could promote the expansion of lung Treg cells in WT mice, but not in iNKT cell‐knockout mice. However, α‐GalCer administration could not boost suppressive activity of Treg cells in WT mice and iNKT cell‐knockout mice. Interestingly, functional inactivation of Treg cells could induce airway inflammation and AHR in WT mice treated with α‐GalCer. Furthermore, α‐GalCer administration could enhance iNKT cells to secrete IL‐2, and neutralization of IL‐2 reduced the expansion of Treg cells in vivo and in vitro. Thus, intraperitoneal administration of α‐GalCer can induce the generation of lung Treg cells in mice through the release of IL‐2 by the activated iNKT cells.

iNKT cells with high PLZF expression are recruited into the lung via CCL21‐CCR7 signaling to facilitate the development of asthma tolerance in mice

“…Recently, a few studies have suggested the potential role of iNKT cells in suppressing asthma inflammation. For instance, iNKT cells could mediate induction of Tregs, this evidence was supported by findings that intraperitoneal administration of α‐GalCer before allergen sensitization could promote the expansion and suppressive activity of lung CD4 + FoxP3 + Treg cells [24‐26]. These effects could suppress regulated Th2‐cell responses and decrease maturation of lung DCs [24].…”

“…The latest studies have suggested that iNKT cells also contribute to tolerance to cow's milk in children [22, 23]. Treatment with alpha‐galactosylceramide (α‐GalCer) combined with CD1d, a specific marker of iNKT cells, before allergen sensitization can prevent T‐helper 2 (Th2) cell responses, promoting iNKT cell‐mediated induction of Tregs and inducing peripheral tolerance in asthma [24‐26]. Thus, PLZF‐expressing iNKT cells might be a novel target for studying asthma tolerance establishment and disruption.…”

Donor Treg expansion by liposomal α‐galactosylceramide modulates Tfh cells and prevents sclerodermatous chronic graft‐versus‐host disease

“…Various studies investigated the mechanisms of how the activation of NKT cells result in Treg recruitment and function and suggested the importance of IL‐4 and IL‐10 in the process 9,10,35 . A recent study demonstrated that activated NKT cells produce IL‐2 which directly acts on Treg homeostasis 26 . Further study will warrant the mechanism more precisely and develop NKT‐based therapy for immune tolerance.…”

“…A shaved skin from the interscapular region (~2 cm 2 ) of recipients was fixed in 10% formalin, embedded in paraffin, sectioned, mounted on slides, and stained with hematoxylin and eosin. Slides were scored by a pathologist (T. T.) on the basis of dermal fibrosis, fat loss, inflammation, epidermal interface changes, and follicular dropout (0–2 for each category, with the maximum score of 10) 26 …”

“…Slides were scored by a pathologist (T. T.) on the basis of dermal fibrosis, fat loss, inflammation, epidermal interface changes, and follicular dropout (0–2 for each category, with the maximum score of 10). 26 …”