PPAR-γ promotes type 2 immune responses in allergy and nematode infection

Abstract

A hallmark of immunity to worm infections and many allergies is a strong type 2 immune response. This is characterized by the production of cytokines interleukin-5 (IL-5) and IL-13 by adaptive T helper 2 (T2) cells and/or type 2 innate lymphoid cells. Peroxisome proliferator activated receptor-γ (PPAR-γ) is typically regarded as an anti-inflammatory factor. We report that T2 cells express high levels of PPAR-γ in response to the allergen house dust mite and after infection with the parasite Mice lacking PPAR-γ in T cells failed to effectively differentiate into IL-5- and IL-13-secreting cells and, hence, did not develop T2 cell-associated pathologies, including goblet cell metaplasia and eosinophilia, in response to allergen challenge. Furthermore, these mice could not mount protective immune responses to nematode infection. In addition, mice lacking PPAR-γ in T cells had greatly reduced frequencies of T2 cells in visceral adipose tissue. Mechanistically, PPAR-γ appeared to promote the expression of the IL-33 receptor on the surface of T2 cells. These results pinpoint PPAR-γ as a factor that drives type 2 responses in allergy, worm infection, and visceral adipose tissue.

PPAR-γ in innate and adaptive lung immunity

“…This effect was particularly apparent in the presence of IL‐33, because PPAR‐γ was absolutely required for ST2 expression and thus IL‐33‐driven Th2 pathogenicity. In addition, recent evidence from another group indicates that PPAR‐γ plays a similar role in CD4 + T cells in parasitic infection, underlining the importance of this transcription factor as a general regulator of Th2 immunity . Furthermore, we could show the relevance of these findings also for humans, because PPAR‐γ was found to be highly expressed in human memory CRTh2 + Th2 cells .…”

“…In addition, recent evidence from another group indicates that PPAR-plays a similar role in CD4 + T cells in parasitic infection, underlining the importance of this transcription factor as a general regulator of Th2 immunity. 39 Furthermore, we could show the relevance of these findings also for humans, because PPAR-was found to be highly expressed in human memory CRTh2 + Th2 cells. 32 These results were corroborated by recent evidence that identified PPAR-as well as CRTh2, IL-5, and IL-9 to be highly expressed in a subset of memory Th2 cells are only present in allergic individuals.…”

PD‐1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator‐activated receptor‐γ

“…PPAR‐γ is a master regulator of adipocyte differentiation and a potent modulator of lipid metabolism, a suppressor of proinflammatory cytokine secretion, and has been being associated with Th2 cell immune responses . In addition, PPAR‐γ has also been identified as a hallmark for ILC2 .…”

“…PPAR-γ is a master regulator of adipocyte differentiation and a potent modulator of lipid metabolism, 33 a suppressor of proinflammatory cytokine secretion, 34 and has been being associated with Th2 cell immune responses. [35][36][37] In addition, PPAR-γ has also been identified as a hallmark for ILC2. 18 Similar to our previous findings, 35 when the PPAR-γ agonist 15dΔ12,14-PGJ 2 (PGJ2) was added to the bmILC2 cultures, there was almost a twofold increase in the expression levels of ST2 on the surface of ILC2 cultured with PGJ2 compared with bmILC2 cultured in the rIL-7 and rIL-33 alone (MFI ST2 115 ± 79 for control Figure 8A).…”

“…[35][36][37] In addition, PPAR-γ has also been identified as a hallmark for ILC2. 18 Similar to our previous findings, 35 when the PPAR-γ agonist 15dΔ12,14-PGJ 2 (PGJ2) was added to the bmILC2 cultures, there was almost a twofold increase in the expression levels of ST2 on the surface of ILC2 cultured with PGJ2 compared with bmILC2 cultured in the rIL-7 and rIL-33 alone (MFI ST2 115 ± 79 for control Figure 8A). When the expression levels of PD-1 were examined, we found that expression of PD-1 was almost doubled on the bmILC2 that were stimulated with PGJ2 (MFI PD-1 245 ± 121 vs 449 ± 280, P < .005 paired t test, n = 7; Figures 8B and S4A).…”