New Kid on the Block: Th17

Dr. Cohen briefly mentioned this newly docuemented subset of T cells in class the other day. I thought I'd follow up on his lecture and give a little more information on the "new kid on the block".

The discovery of Th17 subset came from studies of autoimmune diseases such as experiment autoimmune encephalitis (EAE) and collagen induced arthritis (CIA). Originally people thought these were disease of the Th1 subset. It is understood that dendritic cells produce IL-12, which preferentially selects a Th1 response. Thus, people thought that the autoimmune disease above were Th1 dependent because upon treating with antibodies against the p40 subunit of IL-12, development of EAE and CIA were eliminated. However, in 2000, some extremely clever people discovered that there is a new member of the IL-12 family which shares the common p40 subunit of IL-12. Briefly, most cytokines are made up of separate subunits. Within a class of cytokines, there is a mix and match of these subunits. Therefore, IL-23, the newly described member, utilizes the same p40 subunit, to which neutralizing antibodies eliminated EAE and CIA described above. Upon this discovery, there were a series of mouse experiments carried out where mice deficient in IL-12, IL-23, or both were checked for susceptibility to EAE and CIA. Interestingly, the disease did not develope in mice lacking IL-23, suggesting that EAE and CIA are diseases that are specific to a subset of T cells that, upon stimulated by IL-23, produces IL-17 (this is simplified, of course, a lot of work was done for people to come to this conclusion). Similar to Th1 and Th2, production of cytokines from these two groups block the development of Th17 and vice versa.

IFN-gamma and IL-4 produced by Th1 and Th2 respectively are inhibitory for Th17 differentiation. TGF-beta is an essential growth factor that is required for Th17 differentiation. Historically, TGF-beta is known to have anti-inflammatory activities. They are produced by regulatory T cells and are thought to inhibit Th1 and Th2 activities. Inhibition of Th1 and Th2 activities therefore leads to a lack of IFN-gamma and IL-4 production, allowing for the environment to be permissive for Th17 differentiation. TGF-beta has also shown to push regulatory T cell differentiation. However, these are two distinct subset of T cells. It is thought that differentiation to one of the other is mutually exclusive, therefore a T cell cannot be both a regulatory T cell and a Th17 T cell. In addition to TGF-beta, IL-6 is also essential for Th17 differentiation (and inhibitory for regulatory T cell differentiation) while IL-23 may be important in sustaining the Th17 population.

This subset of T cells is particularly interesting to me. Since TGF-beta is usually an anti-inflammatory molecule (by inhibiting Th1, Th2, and upregulating Treg differentiation), why then is it pro-inflammatory for Th17? In other words, what is the special role that Th17 play? As mentioned before, Th17 are associated with autoimmune diseases and chronic inflammation. If we can inhibit Th17, is that sufficient to completely get rid of the disease? What this subset of T cells has gotten me to wonder is whether or not we can actually group T cells in terms of their subsets, in other words, are there subtle difference between all T cells such that if we just look at the "right" markers, or the "right" cytokines then ALL T cells are in fact in a different subset?

Constantinescu, C.S., et al (1998). Antibodies against IL-12 prevent superantigen induced and spontaneous relpses of experimental autoimmune encephalomyelitis. J. Immunology. 161, 5097-5104.

Oppmann, B., et al (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23 with biological activities similar as well as distinct from IL-12. Immunity 13, 715-725.

Park, H., et al (2005). A distinct lineage of CD4 T cells regulates tissue inflammation by producing Interleukin 17. Nat. Immunology. 6, 1133-1141.

Mangan, P.R., et al (2006). Transforming growth facto-beta induces development of the Th17 lineage. Nature 441, 231-234.

Bettelli, E., et al (2006). Reciprocal developmental pathways for the generation of pathogen effector Th17 and regulatory T cells. Nature 441, 235-238.