July - September 2007: 
Volume 20, Issue 3

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Sexy and 17: Two novel pathways in immune regulation
Keywords: Τreg, Th17, Immunology
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CD 4+ T cells (or T-helper, TH cells) are divided by immunologists, for more than 35 years, into different subsets with distinct profiles and functional characteristics1-3. The idea was that naive T cells differentiate into effector T cells by cytokines produced by cells of the innate immune system under the interaction with the insulting pathogens. CD -4+ effector T cells, under pathogen activation, divide into distinct subsets on the basis of their cytokine production profile and functional characteristics.

Twenty-year ago, the Th1-Th2 paradigm has been proposed1-3 and up to now has provided us with the framework for understanding T cell biology and the relationship of innate and adaptive immunity. The Th1-Th2 hypothesis was proposed after the disappointment of the T-suppressor story. This Th1/Th2 hypothesis dominated our understandings of immune regulation, immune pathogenesis and host defenses for decades, despite its flaws and inability to explain certain data regarding T-cell mediated tissue damage. Th1 responses are typically proinflammatory, necessary to clear intracellular pathogens, while Th2 responses have been considered regulatory and important for clearing extracellular organisms. Sarcoidosis is considered as a classic paradigm of a Th1 immune response, while a Th2 response characterize a number of pulmonary diseases, many of which terminate in tissue remodeling and fibrosis, like idiopathic pulmonary fibrosis (IPF)4 (Figure I).

Recently, two novel CD4 T cell subsets have been described and revolutionized our understanding of immune function. T regulatory cells or Tregs (CD4+CD25+foxp3+) represent the first well defined expansion of the CD4+ T cell functional range5-7. Treg development is specified by the transcription factor forkhead box protein 3 (foxp3), while GATA-3 and STAT1, are the master regulators for Th2 and Th1 differentiation, respectively (Figure II). Foxp3+ expressing CD4+CD25+ Treg, that possess suppressive capacities, can be generated by culture of naive T cells with TGF-b.

Tregs suppress both Th1- and Th2-mediated immune responses in such a way that sufficient immunity remains for clearing infectious agents, while unwanted immunopathology is prevented. In case of shortage of Tregs the potential amplitude of Th1 and Th2 responses is increased, resulting in excessive T cell immunity as associated with autoimmune disease, asthma and allergy, allograft rejection, and some cases of early pregnancy loss. Abundance of Tregs, on the other hand, will reduce the potential amplitude of Th1 and Th2 responses and may prevent adequate immunity to tumours and infectious diseases.Tregs seem to represent the resurrection of the old suppressor T cells. Although of a different phenotype, Tregs are able to suppress many T cell mediated immune responses. A distinction is made between naturally occurring regulatory T cells (nTreg), which require cell-cell contact for suppression, and inducible regulatory T cells (iTreg), which predominantly mediate suppression via cytokine dependent pathways. Only limited studies on Tregs in human disease are available today, but the possible clinical applications are under investigation.

Recently, another CD4 T cell subset has been described,called Th17, which develops via different cytokine signals from those of Th1 and Th2 lineages. Th17 subset is characterized by production of IL-17 and is involved in the pathogenesis of autoimmune tissue injury8-9, including rheumatoid arthritis and allergen-specific responses9. Th17 is the recent and most exciting theory to explain the pathogenesis of these disorders.

The central players to generate new effector CD4+ Th17 subset are TGF-b, IL-23 and IL-17. However, there are still many uncertainties regarding the relation of Th-17 and Th-1 responses in chronic inflammatory and autoimmune disease. Today there is intense research on the Th-17 subsets regarding their role in immune regulation, immune pathogenesis and host defense9-11.

In conclusion, although functional CD4+ T cell development has been dominated by the Th1-Th2 paradigm, the discovery of the Th17 pathway and its relationship with Tregs (Figure 2) opens a new and fascinating era in our understanding of the adaptive immune regulation, resulting in novel and more effective therapeutic approaches in a number of autoimmune and inflammatory diseases.


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