Intestinal helminth skews DC2 development towards regulatory phenotype to counter the anti-helminth immune response
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Abstract
The intestinal immune system maintains a balance between active immunity needed for protection and tolerance towards harmless antigens. Dendritic cells (DCs) found in the intestinal mucosa are key to the adaptive arm of these immunoregulatory events. DCs sample antigens in the tissue and then migrate to the draining lymph nodes, where they prime the T cells that then migrate back to the tissue as effector or regulatory cells. Intestinal DC are highly heterogeneous, and it remains unclear exactly which subsets induces the different kinds of immune response, or what signalling molecules and cellular mechanisms are involved. Here, we have studied these issues using Heligmosomoides polygyrus bakeri (Hpb) infection in mice, a model which is uniquely suited to dissecting this regulatory circuit in the gut, where it drives type 2 protective immunity at the same time as inhibiting other aspects of the immune response. Here, we characterise intestinal DC during Hpb infection for the first time. We observed a dynamical change of intestinal DC populations throughout the course of infection that correlated with altered phenotype and function. In particular, Hpb infection saw a rise in a population of CD103 + DC2 that retained a potent ability to drive Tregs during the infection and unlike CD103-DC2, had a reduced ability to induce pro-inflammatory immune response. Furthermore, transcriptional analysis revealed that TGFβ signalling may be responsible for some of the changes observed. This was confirmed in vitro , where supplementation TGFβ or Hpb -produced TGFβ mimic (TGM) replicated the immunomodulatory effects seen in DCs in vivo . Together, these results present a mechanistic explanation of how helminths such as Hpb may modulate host immune responses by altering the differentiation and function of local DCs. Furthermore, our work provides the basis for understanding immune homeostasis in the intestine at the molecular and cellular levels. Thus, this work fills out a crucial gap in our knowledge of basic biology underlining the DC decision between pro- and anti-inflammatory immune response in the central circuit of adaptive immune response.
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Thus, we concluded that the regulatory, immature phenotype of the CD103+ DC2 found in vivo during Hp infection might be result of TGFβ signalling and likely a result of direct immunomodulatory effect of the TGFβ mimic molecules secreted by Hp.
How similar are naïve DCs generated via in vitro stimulation by human TGF-beta compared to the CD103+ DCs generated by proximity to Hpb granulomas? Do you know whether the helminths are producing other factors, such as additional cytokine mimics, that further bias the phenotype of these DCs?
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Here, we identified that DCs derived in presence of TGFβ had a reduced ability to stimulate T cell proliferation, as measured by CTV
Did you test the effect of TGM on the ability of DC2 cells to stimulate T cell proliferation?
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TGFβ or purified TGM
Do you have any data describing how the specific activities of endogenous TGF-beta and Hpb TGM differ?
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To do this, we took advantage of the fact that at 7DPI, the granulomas approximately half of the size of the Peyer’s Patch and are visible by naked eye
It is certainly fortunate that Hpb infection produces these granulomas. In the case of infections that do not produce this phenotype, how might you have assessed the location-specific effect of helminth infection?
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RA production by both subsets of DC2 was significantly increased during Hpb infection, with this effect being most marked for the CD103- subset
I find it really interesting that Hpb is modulating the specific metabolite production of different subsets of DCs during infection. Do you have any data or hypotheses regarding how Hpb affects the downstream capabilities of specific subsets of DCs once they have differentiated?
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Bioinformatic analysis
Will the underlying scripts and RNA-Seq data for this publication be made available at a later date?
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