Th17 cells are recently found in man and mouse. These cells are important during infections and in autoimmune reactions. Mice are often used to study human diseases and are also used in Th17 cell studies, but differences are found between human and murine Th17 cells. This complicates studying Th17 cells and the targeting of these cells in autoimmune disorders.
CD4+ T helper (Th) cells regulate the immune response towards each particular pathogen. Dependent of the stimulation by dendritic cells or other antigen presenting cells, the effector Th cells promote a Th1 or Th2 response. The type 1 response aims at intracellular pathogens; the type 2 response is targeted at extracellular, parasitic infections (Abbas et al., 1996).
A few years ago, a new subset of CD4+ Th cells was found, distinct from Th1 or Th2 development (Park et al., 2005; Harrington et al., 2005). These cells were discovered in murine autoimmunity models. In these studies, IL-17 mouse knock-outs developed less severe autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis, and collagen induced arthritis (CIA) (Cua et al., 2003; Murphy et al., 2003). Therefore, this subset of cells is called Th17 cells. The autoimmune diseases were first thought to be Th1 mediated (at least in mice), but with the finding of a new cytokine which is not produced by Th1 cells, IL-23, this dogma is revised.
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This Th17 subset is not only distinct in cytokine production, but also in biological function. Th17 cells are considered pro-inflammatory and are important during infection (Ouyang et al., 2008). They recruit and activate neutrophils and macrophages to infected tissues by excreting chemoattractant cytokines and chemokines (Romagnani, 2008). This promotes abscess formation and enhances the expression of antimicrobial peptides (Chung et al., 2003; Kao et al., 2004).
For their development, each Th cell subset requires its own specific set of transcription factors. T-box transcription factor (T-bet) binds the promoter of IFN-ï§ï€¬ an important cytokine in Th1 cell development. GATA binding protein (GATA)-3 changes the epigenetics for Th2 cytokines and thus promotes the Th2 subset (Weaver et al., 2006). In Th17 cells, the most important are retinoid orphan nuclear receptor (ROR) ï§t, which is necessary for IL-17 expression and RORï¡ which promotes differentiation of the Th17 cells (Ivanov et al., 2006; Wilson et al., 2007; Yang et al., 2008).
Before the subset of Th17 cells was discovered, IL-17 was associated in different autoimmunity disorders. In rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease and systemic sclerosis, IL-17 was found (Kotake et al., 1999; Matusevicuius et al., 1999; Wong et al., 2000; Nielsen et al., 2003; Fujino et al., 2003; Kurasawa et al., 2000). Since now is known that Th17 cells are the major source of IL-17, these cells most likely contribute to the pathology and therefore may be a good therapeutic target in various (auto)inflammatory diseases (Awasthi & Kuchroo, 2009).
In the review of Annunziato et al. (2008), the recent findings regarding Th17 cells were reviewed and a differentiation mechanism for Th cells was proposed, including a possible role for TGFï¢. The discovery in humans and mice, phenotype and their role in autoimmune disorders were discussed. The emphasis has been on the differences between human and murine Th17 cells.
The first major difference between murine and human Th17 cells can be found in the cytokines responsible for the Th17 development. In mice, IL-6 and TGFï¢ are thought to initiate specification; in humans IL-1ï¢ and IL-23 are found to be essential in the generation of Th17 cells (Veldhoen et al., 2006a; Mangan et al., 2006; Ivanov et al., 2006; Bettelli et al., 2006). Although TGF-ï¢ is not essential in the development of human Th17 cells, it favours Th17 differentiation and inhibits Th1 and Th2 development (Annunziato et al., 2008).
Another difference is in the Th17 origin. Forkhead box (Fox) P3 is known as important regulator of regulatory T cells (Tregs), but also regulates the murine Th17 development (Lochner et al., 2008; Ichiyama et al., 2008; Zhou et al., 2008). In addition, TGF-ï¢ is known to promote Treg development, but is also essential for the generation of Th17 cells (Hori et al., 2003; Fontenot et al, 2003; Veldhoen et al., 2006b). This implies that murine Th17 cells share homology with Tregs. The origin of human Th17 cells differs from the Th17 cells in mice. In humans, Th17 cells originate from a small subset of CD161+CD4+ T-cell precursors that can also give rise to Th1 and Th2 cells (Cosmi et al., 2008).
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Third, Th1 cells seem to play a protective role in mouse models of autoimmunity, in contrast to the pathogenic Th17 cells (Ferber et al., 1996; Weaver et al., 2006). However, in humans both Th1 and Th17 are involved in the pathogenesis of autoimmune diseases (Annunziato et al., 2008).
Finally, human cells can be characterized by CC chemokines receptor (CCR) 6, IL-23R, IL-12Rï¢2 and CD161 (Romagnani et al., 2009). In contrast, the Th17 cells of mice do not express NK1.1, the murine equivalent of CD161 (Michel et al., 2007; Pichavant et al., 2008).
The differences between human and murine Th17 cells mentioned in this review article were all known on beforehand. But it was the first article that shows the importance of being careful extrapolating results found in mice to humans in Th17 studies and compares the results of mouse experiments to human studies in the Th17 research field. Differences in features, origin and role in immunopathology are found. This implies that studies in mice are possibly not comparable to the situation in human autoimmune diseases.
This article shows another example that mouse models are not always suitable for studying human diseases. But it also describes the origin, generation and function of Th17 cells, in healthy people and patients, in human and mice. This makes it a complete and elaborate review article containing all literature known about Th17 cells in 2008.
Although the article emphasis on the differences between human and murine Th17 cells, these differences may be not as big as described in the abstract is suggested. A recent paper from Ghoreschi et al. (2010) showed that induction of murine Th17 cells is possible without TGFï¢. In this study, Th17 cells are generated with IL-1ï¢ï€¬ IL-6 and IL-23. They conclude there probably is an alternative pathway in which IL-23 is important. This recent finding implies that most likely the differentiation into Th17 cells in mice is not that different from the specification in humans and a similar pathway may exist.
Second, the protective role of Th1 in mice is not without controversy. This is also mentioned shortly in the paper, but this possible protective role is stated in the abstract of the review. Because the protective role of Th1 cells is questionable and this is acknowledged in the article, this argument as differences between murine and human Th17 cells is not convincing.
Missing in the article are the data found in studies with autoimmune mouse models. These data agree with observations in human autoimmune diseases (Torchinsky & Blander, 2010). Therefore, the mouse model mimics human disease and this suggests applicability of the mouse model for studying human diseases.
Concluding, the differences between man and mice are probably not that big as described in the abstract of the article from Annunziato et al. (2008). But in this same review, the authors describe perfectly the generation, origin and function of Th17 cells. This makes it an excellent review to get a good overview in this field.
In the paper of Annunziato et al. (2008), the question arises: should mouse models be used in this area of research, since there are differences in human and murine Th17 cells. In my opinion mouse models can be used to study the role of Th17 cells in human diseases. They have proven to be useful in many diseases and they are necessary to study the mechanisms of the diseases. Unfortunately, it is still not possible look at organ structures without damaging the body, so mouse models are the only option to study the organs. Another advantage of using mice is the possibility to generate knock-outs. In these knock-out mice, one gene is switched off and not expressed any more. The disorders that may develop provide information about the gene function.
Although mouse models are very useful, animals are sacrificed and suffer during these studies. This makes the use of animals is controversial and therefore animal studies should be limited. In Th17 cell studies, mice are necessary to prove the role of Th17 cells in autoimmune disorders and provide insight in the mechanisms involved. For these studies, mouse models are the optimal model. In cell cultures the disease cannot be mimicked and in humans, only biopsies from lesions can be used and this makes it difficult to study. Therefore I think that mouse models essential to answer the question on the role of Th17 cells in human autoimmune diseases despite the differences compared with humans.
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