Klf4 Expression in Conventional Dendritic Cells Is Required for T Helper 2 Cell Responses

Abstract

Summary The two major lineages of classical dendritic cells (cDCs) express and require either IRF8 or IRF4 transcription factors for their development and function. IRF8-dependent cDCs promote anti-viral and T-helper 1 (Th1) cell responses, whereas IRF4-expressing cDCs have been implicated in controlling both Th2 and Th17 cell responses. Here, we have provided evidence that Kruppel-like factor 4 (Klf4) is required in IRF4-expressing cDCs to promote Th2 but not Th17 cell responses in vivo. Conditional Klf4 deletion within cDCs impaired Th2 cell responses during Schistosoma mansoni infection, Schistosoma egg antigen (SEA) immunization, and house dust mite challenge (HDM), without affecting cytotoxic T lymphocyte (CTL), Th1 and Th17 cell responses to herpes simplex virus, Toxoplasma gondii and Citrobacter rodentium infections. Further, Klf4 deletion reduced IRF4 expression in pre-cDCs and resulted in selective loss of IRF4-expressing cDCs subsets in several tissues. These results indicate that Klf4 guides a transcriptional program promoting IRF4-expressing cDCs heterogeneity.

Kruppel-like factor 4 regulates neutrophil activation

“…17 More recently, in the context of DC biology, KLF4 deficiency was found to significantly attenuate the development of the interferon regulatory factor 4-expression convectional DCs, leading to impaired Th2 immunity. 18 The current findings that include cell-based and in vivo studies strongly suggest that KLF4 deficiency attenuates neutrophil proinflammatory activation. The fact that KLF4 appears to have differential effects on myeloid cell development and activation suggests that the underlying transcriptional mechanisms mediated by KLF4 are unique in each cell type because of specific cellular context.…”

“…14 In particular, our group and others identified KLF4 as an essential transcriptional regulator of myeloid cells, including monocytes, macrophages, and dendritic cells (DCs). [15][16][17][18] However, its role in neutrophils remains completely unknown. Here we show multiple lines of evidence supporting that KLF4 is requisite for neutrophil biology.…”

Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans

“…In addition, CCR7 + CD1c + MDCs in BAL unlike the CCR7 2 counterparts expressed lower levels of CCR2 and higher levels of IRF4. CCR2, in addition to being a peripheral tissue homing receptor (47, 48), has been shown to be important in DC-elicited Th1 responses (59), whereas IRF4 has been implicated in both Th2 (49,(60)(61)(62) and Th17 responses (26,63). Taken together, this underlines the phenotypic and likely functional heterogeneity of DCs in the lungs, even within one population of CD1c + MDCs.…”

Lung CD103+ dendritic cells restrain allergic airway inflammation through IL-12 production

“…Plasmacytoid DCs play a key role in the induction of Tregs that control exacerbated airway inflammation (9). CD11b + cDC2s mediate Th2 priming in response to house dust mite (HDM) and to Blomia tropicalis mites (10)(11)(12), leading to eosinophilic airway inflammation, mucus production, and AHR. CD11b + cDC2s also promote a Th17 response upon lung fungal infection with Aspergillus fumigatus (13).…”