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.
Highlights
Antigen (Ag)-presenting cells (APC) instruct CD4+ helper T (Th) cell responses, but it is unclear whether different antigen-presenting cells (APCs) subsets contribute uniquely in determining T helper (Th) differentiation in pathogen-specific settings
Besides individual APC populations having a role in driving specific types of CD4+ T cell responses, there is evidence that APC exposed to appropriate stimuli can display a degree of functional plasticity to induce different types of responses[13,14,15,16]
By using mutant mouse strains that are defective in either migDC2 or monocytes, we report that the same population of dermal migDC2 can take up different pathogens and support the optimal differentiation of CD4+ T cells producing IFNγ, IL-4, or IL-17A, whilst monocytes are essential for early innate IFNγ production and full Th1 differentiation after bacterial immunization
Summary
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. Through the expression of pattern recognition and cytokine receptors, antigen-presenting cells (APCs) perceive pathogens while sensing the response of bystander cells to the same stimuli[4], thereby conveying the sum of these signals to initiate the appropriate CD4+ T cell differentiation program. Epidermal Langerhans cells (LC) and blood-borne classical Ly6Chi monocytes may participate in driving CD4+ T cell responses The presence of such a diverse repertoire of APC has led to the proposal that APC populations may specialize in promoting certain CD4+ T cell differentiation programs, a notion that is supported by the differential expression of key cytokines and co-stimulatory molecules by different DC subsets Besides individual APC populations having a role in driving specific types of CD4+ T cell responses, there is evidence that APC exposed to appropriate stimuli can display a degree of functional plasticity to induce different types of responses[13,14,15,16]
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