Sunday, April 20, 2014

CD4 T cells need to have their cake and eat it too to become Th17

     I want to review two new and complementary papers addressing natural specificity of gut Th17 cells. One paper was published in Immunity and came from Ivaylo I. Ivanov's Lab (1) and second one was published in Nature and came from Dan Littman's Lab (2). This is not surprising since Ivaylo I. Ivanov is Dan Littman's former postdoc who was the first author in original paper discovering relationship between segmented filamentous bacteria (SFB) and IL-17 producing T helper cells.

     To understand significance of these papers one needs to remember that proper development of immune system requires presence of gut microbiota. Some of this microbes induces development regulatory T cells and some of them can induce development Th17 cells.
     These papers address the role of SFB antigen in driving Th17 induction. In Immunity paper, the authors first showed that induction of new Th17 cells requires class II (MHCII) expression on host cells. However, since CD4 T cells will need to interact anyway with MHCII just to become properly activated, result is not surprising or even relevant. Second, they used adoptive transfer of TCR transgenic CD4 T cells on RAG KO background to reveal that antigen alone or SFB alone is not sufficient to promote Th17 conversation from random T cells. Third, to understand the specificity of Th17 cells, the authors utilized IL-17-GFP reporter mice and prepared hybridomas from GFP+ and GFP- T cells and stimulated them with different gut microbial lysate or alternatively with purified SFB. The vast majority of GFP+ cells (consisting of natural Th17 cells) responded to SFB antigen. Lastly, the authors showed that MHCII expression on dendritic cells was necessary and sufficient to induce Th17 cells.
     Nature paper went further to analyze SFB antigen recognized by Th17 cells. They utilized IL-23R-GFP reporter mice that labels natural occurring IL-17 producing T cells. The authors generated hybridomas that specifically recognized two SFB antigen nominally named SFBNYU 3340 and SFBNYU 4990. Based on hybridoma specificities, the authors generated several transgenic mice expressing SFB-specific TCRs. Adoptive transfer experiment revealed that upon transfer almost all donor SFB-3340 specific T cells started to express Th17 specific transcription factor, RORgt. Interestingly, SFB antigen itself did not drive the polarization into Th17 cells since its expression in Listeria Monocytogenes (Listeria-3340) induced typical Th1 response. Moreover, dual colonization of mice with SFB and Listeria did not affect differentiation of Th17 driven by SBF.
    In summary, these studies showed that SFB colonization induce Th17 cells in antigen and context dependent manner. The most likely scenario involves gut dendritic cells internalizing SFB and expressing its antigen to CD4 T cells to drive their polarization towards Th17.

     These studies reveal that even though gut microbiota is made of diverse species, few species have extraordinary effect on development of immune system. This implies that there is some evolutionary pressure for development of such cohabitation. The knowledge that particular bacterial specie can drive particular polarization of T helper subset even in presence of competing polarization programs (SFB vs. Listeria) could lead to development of natural gut flora based medicine (transgenic microbial flora) to treat many autoimmune and allergic diseases.


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