For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. The Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4 + T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4 + T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells. The Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines.
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Interestingly, it has been reported that there is not only a cross-regulation among Th1, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-β or TGF-β plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.
An efficient adaptive immune response against pathogen antigen determinants is fundamental for their elimination by the host. At the same time, it is also crucial for host homeostasis that the immune system is able to tolerate self-components, as well as many foreign antigens, such as those from commensal bacteria and food.
Uncovering the mechanisms that enable the adaptive immune system to accomplish these tasks has always (and still is) been a big challenge. That was exactly the challenge motivating Christopher Parish's research when he drew the basis for the later establishment of the Th1/Th2 paradigm. Parish was employing antigen modification by acetoacetylation to induce tolerance. He found that acetoacetylated derivatives of flagellin (from Salmonella adelaide) were able to dramatically reduce a primary antigen response to unmodified flagellin in rats. Unexpectedly, the same antigen modification led to an increased delayed-type hypersensitivity (DTH) response. Thus, there was an inverse relationship between antigen response and DTH. Although the term 'immune deviation' had been coined a little earlier, that was the first strong evidence showing that humoral- and cell-mediated immune responses could be cross-regulated.
One important question still remained: Are the T cells mediating DTH different from those helping B cells to produce antibodies? Although Parish and Liew performed experiments suggesting the existence of different T-cell populations orchestrating humoral- and cell-mediated responses, a formal proof was still missing. It is important to keep in mind that at that time there were no monoclonal antibodies to surface markers and cytokines. Actually, the discovery of cytokines was about 10 years away and even distinguishing CD4 and CD8 cells was not as easy as it is today. In the mid-1980s, the development of new techniques, such as the ability to clone T cells, and the MTT assay, a colorimetric assay for cell growth, allowed this question to be revisited. By combining these two new tools, Tim Mossman's lab was able to distinguish two different types of T cells producing different growth factors.
While Th1 cells would mainly produce IL-2 and IFN-γ, Th2 cells would produce a weaker T-cell growth factor distinct from IL-2,. At the same time, Bob Coffman's lab had established a very sensitive and specific solid-phase assay for IgE, aiming at understanding how IgE production is regulated. The two lines of research came along very nicely when they decided to test supernatants from the two different T cell types in their assay for IgE production. Surprisingly, supernatants from a Th2 clone added to LPS-stimulated B cells led to robust IgE responses, whereas supernatants containing IL-2 and IFN-γ from Th1 clones induced no IgE production,. Importantly, when both supernatants were added together no IgE was detected, demonstrating the ability of a Th1 factor to block the Th2-induced IgE response. By using neutralizing antibodies (the only monoclonal antibody to a cytokine they had available at that time), they demonstrated that the Th1 factor responsible for inhibiting Th2-induced IgE production was IFN-γ,. It was also found that the weaker T-cell growth factor released by Th2 clones that could induce IgE responses was actually IL-4, called B-cell stimulatory factor-1 (BSF-1) at that time,.
One year later, the last piece to build up the concept came when it was demonstrated that Th1 clones, but not Th2 clones, could mediate DTH responses. The Th1/Th2 paradigm implies the existence of two different CD4 + T helper subsets. One of them, Th1, drives cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites and also provides help for B cells to produce certain isotypes of G immunoglobulin (Ig), specifically IgG2a,. The other one, Th2, mediates IgE production and is largely involved in eosinophilic inflammation, allergy and clearance of helminthic infections,. The concept also involved the notion that the two subsets are cross-regulated. Thus, cytokines released from cells of one subset had the ability to stimulate its own subset in an autocrine fashion and, at the same time, inhibit the other subset. The studies on the Th1/Th2 paradigm rapidly evolved to understand better what determines the differentiation of each subset and also the transcription factors involved in their regulation.
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Accumulating evidence shows that IL-12 is crucial for Th1-cell differentiation through Stat4 (signal transducer and activator of transcription 4) and the activation of a unique transcription factor named T-bet (T-box expressed in T cells), which upregulates IFN-γ and downregulates IL-4 and IL-5 expression,. In contrast, IL-4 induces Th2-cell differentiation through Stat6 and activation of GATA3, which upregulates IL-4 and IL-5, but downregulates IFN-γ expression,. The Th1/Th2 paradigm proposed by Mosmann and Coffman had a profound impact on the way immunologists perceived adaptive immune responses and the reciprocal relationships that might exist among T-cell subsets. It has also helped our better understanding of factors that regulate atopic diseases as well as host resistance and susceptibility to intracellular pathogens such as Leishmania major.
Following the “fall” of suppressor T cells, it was also proposed to explain peripheral tolerance to self-components.