Dermal IRF4+ dendritic cells and monocytes license CD4+ T helper cells to distinct cytokine profiles

Abstract

Antigen (Ag)-presenting cells (APC) instruct CD4+ helper T (Th) cell responses, but it is unclear whether different APC subsets contribute uniquely in determining Th differentiation in pathogen-specific settings. Here, we use skin-relevant, fluorescently-labeled bacterial, helminth or fungal pathogens to track and characterize the APC populations that drive Th responses in vivo. All pathogens are taken up by a population of IRF4+ dermal migratory dendritic cells (migDC2) that similarly upregulate surface co-stimulatory molecules but express pathogen-specific cytokine and chemokine transcripts. Depletion of migDC2 reduces the amount of Ag in lymph node and the development of IFNγ, IL-4 and IL-17A responses without gain of other cytokine responses. Ag+ monocytes are an essential source of IL-12 for both innate and adaptive IFNγ production, and inhibit follicular Th cell development. Our results thus suggest that Th cell differentiation does not require specialized APC subsets, but is driven by inducible and pathogen-specific transcriptional programs in Ag+ migDC2 and monocytes.

The skin environment controls local dendritic cell differentiation and function through innate IL-13

“…The increased responsiveness of CD11b low DC2s to TSLP (Ochiai et al, 2014), an epithelial cytokine with a known role in promoting Th2 responses (Ziegler, 2012) may underpin this observation. In addition, the higher expression of several Tlr transcripts in CD11b hi compared to CD11b low DC2s suggests a lower responsiveness of CD11b low DC2s to microbial stimuli, which was observed in our previous study (Hilligan et al, 2020) and is a likely consequence of IL-13 signaling (Leyva-Castillo et al, 2020), providing a plausible mechanism for the increased IL-17A and ROR γ t+ responses in IL-4Rα conditional KO mice.…”

“…Compared to Il4ra f/- mice, AF488 + cells in Il4ra f/- zDC-Cre mice comprised a lower number of DC2s which were mainly CD11b hi , and an increased number of monocytes ( Figure S5E-G ). As monocyte depletion does not affect IL-4+ Th response to Nb (Hilligan et al, 2020), this increased monocyte response is unlikely to contribute to the Th response in Il4ra f/- zDC-Cre mice.…”

“…In contrast, MHCII-competent DCs originated from CD45.2 + BMs and were either STAT6-KO and unable to respond to IL-13 signaling in the test chimeras, or WT and responsive to IL-13 in the control chimeras ( Figures 5B and S5A-C ). All chimeras were immunized intradermally with inactivated pathogens that induced either Th1, Th2 or Th17 responses (Blecher-Gonen et al, 2019; Hilligan et al, 2020) and CD4 + T cell cytokine production was assessed in the skin-dLN five days later. IFN γ + responses induced by Mycobacterium smegmatis ( Ms ) immunization were detectable at similar levels in both C57 and STAT6-KO mixed BM chimeras ( Figure 5C ).…”

“…Mice were anesthetized with 100 µg/g body weight Ketamine and 3 µg/g body weight Xylazine (both Provet) by intraperitoneal injection and injected with 4×10 6 CFU heat-killed Ms , 1×10 7 heat-killed Ca or 300 non-viable Nb L3 larvae in 30 µl PBS intradermally in the ear pinna as previously described (Hilligan et al, 2020). PBS was injected into the ear pinna of control animals.…”

Conversations that count: Cellular interactions that drive T cell fate

“…While relatively scarce in secondary lymphoid organs, monocyte-derived dendritic cells (moDCs) can induce both T H1 and T H17 responses. 133,145,146 Further, moDC promotion of T H1 differentiation is associated with their location in IFRs following vaccination. 137 Recently, Bosteel et al provided an important advance to the dendritic cell literature, revealing that these cells are not capable of antigen processing; however, they can express high levels of IL-12 to polarize effector T cells.…”