Saturday, October 31, 2009

Th17 cells

I can well remember when immunologists did not know what the lymphocyte did - our anatomy professor was certain that they turned into red cells. I remember the excitement when Roger Taylor and others set about separating lymphocytes into T cells and B cells. It wasn't long before T cells were divided into helper cells and cytotoxic cells. Then more recently T helper cells were separated into Th1 which helped the cellular immune response and Th which helped the antibody response.

I was sitting in a lecture 10-15 years ago when I heard Ethan Shivak explain that there was a regulatory T cell that was CD4+, CD25+ (and later FOXP3+). Well more recently three more types of T cells have been described: Th17, Tfh and Th. A recent review of T cells can be found here .

Th17s are cells that produce interleukin (IL) 17A, IL-17E and IL-17F. These are pro-inflammatory cytokines. They also produce IL-21 and IL-22. What are they for? They seem to be involved in fighting off certain unusual infections. For example, Th17 cells have been suggested to contribute to the resistance to Listeria, Salmonella, Toxoplasma, Cryptococcus, Leishmania and Francisella. A significant and specific role for the Th17 response has been shown for Klebsiella infection in the lung, intravenous Candida albicans infection, and infection of the natural rodent pathogen Citrobacter rodentium in the gut. In addition, the preferential production of IL-17 by T cells during infection with Bacteroides fragilis, Borrelia burgdoferi, Mycobacterium tuberculosis and fungal species suggests that Th17 responses are triggered by specific pathogens and are required for their clearance. Older readers may recognise that some of these these are important in immunodeficient individuals.

In addition to controlling infection, Th17 cells play an important role in autoimmunity. IL-17 expression has been associated with autoimmune diseases such as multiple sclerosis, Rheumatoid Arthritis, psoriasis and Inflammatory Bowel Disease, as well as with allergic responses. In particular, Th17 cells are critical for the development of experimental autoimmune encephalomyelitis and an experimental Rheumatoid Arthritis, whose development was originally attributed to Th1 cells before the discovery of Th17 cells.

How are Th17 cells produced? We know that TGF-β and IL-6 act together (and both are necessary) to commit naive T cells to develop into Th17 cells. and MyD88-dependent signaling, which proved to be IL-6. TGF-β alone tends to favor the production of Tregs but the addition of IL-6 redress that tendency and pushes the cells toward Th17 development.

IL-23 and IL-21 are cytokines shown to be important for Th17 differentiation. IL-23 is currently thought to be critical for promoting the survival and proliferation of differentiated Th17 cells. IL-23 uses one of the same chains as IL-12 and in some respects as reciprocal activity. It binds to the IL-23R complex composed of IL-12Rβ1 chain and a novel receptor chain (IL-23R) related to IL-12Rβ2 and gp130. Jak2/Tyk2-STAT1, 3, 4, and 5 are involved in its intracellular signal transduction. In contrast to IL-12, IL-23 predominantly activates STAT3, but not STAT4.

IL-21 is an IL-2 family member that was recently found to be highly produced by Th17 cells. IL-21 can substitute for IL-6 to induce Th17 cells along with TGF-β. IL-21-activated signaling pathways critical for Th17 differentiation and its biological function under physiological and pathological conditions remain to be established.

Retinoic acid-related orphan receptors (ROR) are the key transcription factors in Th17 differentiation.

Soon after the discovery of Th17 cell scientists wanted to know how it related to other Th cells. Based mostly on the studies in vitro, Th17 and iTreg were found to be mutually exclusive. Following activation in the presence of TGF-β, CD4 T cells differentiate into Foxp3-expressing iTreg without IL-17 expression. However, if IL-6 is also present, activated CD4 T cells deviate to Th-17 cells without Foxp3 expression. The mechanism of such a mutual exclusion could be owing to Foxp3 expression in iTreg and ROR-t expression in Th17 cells. It appears that high-level Foxp3 expression leads to the repression of ROR-t and thus Th17 differentiation, and ROR-t expression inhibits Foxp3 and prompts IL-17 production.

Recently, emerging evidence suggests that under certain conditions, seemingly committed T cells possess plasticity and may convert into other types of effector cells. Tregs can become Th17 cells in the presence of activated inflammatory Dendritic Cells through the action of IL-6. Seemingly fully differentiated Th17 cells were also shown to convert into Th1 cells in the absence of TGF-β.

I suggest a good read of the article I cited if you want to find out about Th9 and Tfh cells. indeed it will bring you up to date on T cells activity.


Anonymous said...

What a wonderful (though intimidatingly complex) system of cellular function modified by cytokines.

I fear that it will take prodigious work, but anticipate that the day will come when the "plasticity" of Th cells can be exploited to alter the course of neoplastic, autoimmune and infectious diseases...if only my birth had been delayed for several decades!


Anonymous said...

They were right when they said the immune system is the most complex system in the human body, after the brain. It's getting hard to keep track of all of the players.

Do any of these bear upon CLL proliferation? I recognize ROR as a receptor supposedly is found in CLL cells, but not commonly elsewhere in the adult body. I believe it was referred to as a onco-fetal gene or some such.