Ikaros Plays an Important Role in the Th17 Response

Autoimmune diseases are a sections of diseases with which we are struggling to find a cures, and if we can learn more about them, then we are likely to solve resolve this issue.  That is why this article was so interesting.  It talks about a specific lineage of T-helper (Th) cells, Th17 cells, and a protein, Ikaros, that can lead the naïve Th cells towards a Th17 response.  Before we jump into the article, though, some important background information is necessary.

The exact function of Th17 cells are though to be involved in autoimmune and tumor cell response¹, so how are these Th17 produce? After a naïve Th cell is activated by signals 1, 2, and 3, it can choose to illicit one of three different responses based upon the cytokines present within its surrounding environment: Th1, Th2, or Th17¹.  (If you’re interested in learning more about Th1 or Th2 responses check out this link) In order to become a Th17 cell, the activated Th cell must be exposed to IL-6  and TGFβ to differentiate¹.  After differentiation is complete, the now Th17 cell releases its own cytokines, IL-17 and IL-6, to cause an immune response¹.  For the visual learners, here’s an image that depicts this as well:

 

Peterson, David. "Am I TH1 or TH2 or TH17?" Living Wellness. N.p., 12 Oct. 2012. Web. 05 Nov. 2013. <http://livingwellnessblog.wordpress.com/2012/10/12/am-i-th1-or-th2-or-th17/>.

Another type of immune system cell is regulatory T (Tregs) cells which help to control the ongoing immune responses¹.  Additionally, Foxp3 is a necessary transcription factor that allows for proper development and function of Tregs which, when functioning properly, can inhibit the Th1, Th2, and Th17 response¹. 

The first experiment performed demonstrated that Ikaros contributed to Th17 cell differentiation².  This was tested by exposing wild type and Ikaros lacking mice to Th17 cell polarizing conditions and measuring the production of IL-17 since IL-17 is produced by Th17 cell².  Mice lacking Ikaros had consistently lower levels of IL-17 demonstrating that Ikaros is related in some way to Th17 cell development².

However, it could be possible that Ikaros lacking mice are developmentally impaired in the thymus, which means that removing Ikaros prevents the creation of functional leukocytes². This could explain the lower levels of cytokines produced by Th17 cell instead.  In order to disprove this theory, wild type cells were infected with a retrovirus containing the gene sequence for the dominant-negative isoform, Ikaros-7, and cultured under Th17 cell polarizing conditions².  It was then shown that Ikaros-7 treated cells displayed similar patterns to cells lacking Ikaros which means that the low levels of IL-17 can be attributed to the lack of Ikaros and not potential developmental problems that could have been present within Ikaros lacking cells². 

The effect of Ikaros on Treg cells was also tested since the expression of Foxp3, which is responsible for Treg cell development and the expression of cytokines that inhibit Th17 cell function, was elevated².  Therefore, Ikaros lacking cells were exposed to Treg cell polarizing conditions and the expression of Foxp3 was measured².  There was strong expression in wild type cells but not in Ikaros lacking cells; this indicates that Ikaros is also necessary for proper Treg cell development and its function is dependent upon the cytokine environment². 

A final experiment was run to determine if natural Th17 (nTh17) cells expressed the same cytokines as induced Th17 (iTh17) cells in the absence of Ikaros since nTh17 cells gain their effector function within the thymus.  It was determined that IL-17 expression was not affected². 

As we learn more about the Th17 cell response, we could shed light onto possible causes and solutions to autoimmunity which would improve the lives of many people globally.

Primary Source:

1. Wong, Larry Y., Julianne K. Hatfield, and Melissa A. Brown. "Ikaros Sets the Potential for Th17-lineage Gene Expression through Effects of Chromatin State in Early T Cell Development." Journal of Biological Chemistry (n.d.): n. pag. The Journal of Biological Chemistry. American Society for Biochemistry and Molecular Biology, 21 Oct. 2013. Web. 2 Nov. 2013. <http://www.jbc.org/content/early/2013/10/21/jbc.M113.481440>.

Secondary Source:

2. Mak, Tak W., Wendy L. Tamminem, Maya R. Chadda, and Mary E. Saunders. Primer to the Immune Response: Academic Cell Update. Burlington: Academic, 2011. Print.