Microbiota, IL-1β and Th17

After writing my last entry I started deliberating over possible mechanisms that may stay behind the unusual activation status of CD69-positive CD4 T cells that reside in colonic lamina propria. As you remember the presence of commensal microbiota is critical for CD69 up-regulation on CD4 T cells. CD69-positive lymphocytes are also induced into peculiar state of immune unresponsiveness which may be one of mechanisms responsible for intestinal tolerance. Additionally, studies with OVA transgenic strains have shown that colonic CD4 T cells may be able to attain this state in the TCR-independent way. I have found the publication describing microbiota-dependent signaling axis involved in the development of Th17 effector subset in the gut that might be useful for possible elaboration of these findings.

The link:
http://jem.rupress.org/content/209/2/251.abstract

Th17 is the effector population of CD4 T cells that tends to accumulate inside the gastrointestinal tract in response to commensal microbiota. Furthermore, these cells play the important role in a number of inflammatory and autoimmune conditions. The induction of Th17 in pathogenesis requires several cytokines such as IL-1β, IL-6, IL-23 and TGF-β1. However, it is still not clear which of these factors are necessary for homeostatic intestinal Th17 generation. This publication employs an in vivo reporter system tracking the expression of Th17 lineage-specific transcription factor Ror γt as a marker of Th17 effector population. By analyzing mice deficient in relevant cytokine/cytokine receptors (IL-6, IL-1β and IL-1R) or intracellular signaling (MyD88) authors seek to determine what particular components are necessary for steady-state Th17 intestinal response.

Data indicate that IL1R-MyD88 signaling axis on CD4 T cells is an essential part in developing full-blown Th17 reaction in the gut. According to obtained information MyD88-dependent circuitry can be used twice in the pathway leading to intestinal Th17 generation – first on macrophages that react to conserved molecular patterns derived from microbiota and release IL-1 β; second time on CD4 T cells that bind IL-1 β through IL-1R and activate downstream signaling to become Th17 effector population. In contrast, IL-6 is not needed for steady-state non-inflammatory Th17 level. Authors also identify the macrophage population (CD11b+F4/80+CD11c-/low) as the main source of intestinal IL-1β cytokine.

I wonder how these data might be useful in elaboration of results obtained in CD69-related account. It may be a good idea to check whether the steady activation status of OVA transgenic CD4 T lymphocytes in the colon could be maintained when there is no IL-1R/MyD88 signaling axis on these cells. Other than that this paper is very interesting addition to still developing Th17 story in the gut. For me particularly remarkable is the hint at possible distinction between mechanisms of homeostatic Th17 induction (no IL-6 needed) versus inflammatory Th17 response (with IL-6). It is also not the first suggestion that there may be more than one way to generate IL-17A releasing CD4 T cells – the December issue of Immunity contains the report describing differences in Th17 priming between spleen and gastrointestinal tract. Interestingly, both papers claim that IL-1R/MyD88 signaling axis is important for successful Th17 induction. They disagree, however, about the intestinal role of IL-6 with one paper asserting it dispensable but the other necessary.

What is the homeostatic role of Th17, though? How does it relate to the maintenance of intestinal tolerance? We know quite a lot about Th17 involvement in pathogenesis (here understood either as protection against assaulting bacteria/fungi or aggravation of autoimmune conditions) but much less information is available regarding its steady-state presence. Yet there are some interesting facts to build on. For example, mice are inhabited by the group of microorganisms called segmented filamentous bacteria that can specifically prime Th17 response. These bacteria are non-cultivable and appear to exhibit extreme adaptations for intestinal environment. The gut milieu also seems to be able to enforce the regulatory phenotype on Th17 cells and reduce their pathogenic potential. It is possible that the microbiota-Th17 link may reveal more of its hidden enigmas.

Shaw MH, Kamada N, Kim YG, & Núñez G (2012). Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine. The Journal of experimental medicine, 209 (2), 251-8 PMID: 22291094

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3 Comments

  1. Aleksandra

     /  April 10, 2012

    Krzysiek, have you seen this publication:

    http://www.ncbi.nlm.nih.gov/pubmed/22442383

    I’m reading it right now 🙂

    Great blog!
    Ola

    Reply
  2. Thanks for info, Ola. I haven’t seen it yet.

    Krzysiek

    Reply
  1. Mononuclear phagocytes and the intestinal tolerance « Memory Reactivation

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