ReviewTh17 and regulatory T cell balance in autoimmune and inflammatory diseases
Introduction
The immune system with its innate and adaptive components has developed to defend the body. Its principal functions are the recognition with subsequent elimination of foreign antigens, induction of immunologic memory, and development of tolerance to self-antigens. T-lymphocytes by mediating the cellular immunity provide adaptive immunity. CD4 + T cells after being activated and differentiated into distinct effector subsets play a major role in mediating immune response through the secretion of subset-specific cytokines. Any defect in the T cell populations may result in diseases and autoimmune diseases are result from failure to sustain tolerance to self and/or cross-reactive molecules. Depending on the cytokines they produce, these T cell subsets have very different properties. Helper T cells (Th cells) include the well-defined effector Th1 and Th2 subsets as well as the more recently described Th17 cells, but also regulatory subsets like regulatory T cells (Treg cells).
The Th17 and Treg developmental pathways are reciprocally interconnected. This implicates a balance between both cell types which influences the outcome of the immune responses. Research on the immunopathogenesis of autoimmune and inflammatory diseases has made significant progress in the past few years and Th17 and Treg cells have emerged as major players in autoimmunity. Th17 cells represent a pro-inflammatory subset, which when in excess contributes to autoimmunity and tissue damage whereas Treg cells have an antagonistic effect, which when in failure also contributes to the same diseases. The Th17/Treg balance provides a basis for understanding the immunological mechanisms that induce and regulate autoimmunity and chronic inflammation.
In this review, we will give an overview of the biology of Th17 and Treg cells and their role in autoimmune diseases, with special focus on rheumatoid arthritis and multiple sclerosis, as well as how these subsets may represent new targets for treatment.
Section snippets
Description of the cell subsets
The cells of the innate immune system are the first line of defense against pathogens. CD4 + T cells have a major role in the initiation of immune responses. They provide help to other cells and take on a variety of effector functions. Upon antigenic stimulation, naive CD4 + T cells become activated, expand and differentiate into different effector subsets. Distinct types of Th cells are based on the produced cytokines and effector functions. Regarding infections, Th1 and Th2 provide effector
Treg cells
Regulatory T cells are a subset of CD4 + lymphocytes that were originally termed “suppressor cells” [26]. These cells play an important role in the maintenance of self-tolerance and in the modulation of overall immune responses against infections and tumor cells. Treg cells secrete TGF-β and IL-10 and require the specific cytokine TGF-β and the transcription factor FoxP3 for their differentiation. They inhibit autoimmunity; they are responsible for tolerance against self-antigens, and protect
Other subsets
Accumulating evidence indicates that CD4 + T cells are more plastic than previously described, particularly Treg and Th17 cells. Thus, additional subsets have been described between these two extremes.
Th17/Treg balance
Th17 and Treg cells have opposite roles in the development of autoimmune and inflammatory diseases. While Th17 cells promote autoimmunity, Treg cells serve to control it and therefore play a very important role in autoimmune pathogenesis by maintaining self-tolerance and by controlling expansion and activation of autoreactive CD4 + T effector cells. The control of Th17/Treg balance appears also critical in the development of these diseases. Furthermore, developmental pathways of Th17 and Treg
Therapeutic applications
Regarding the pathogenic mechanisms of RA, the Th17/Treg imbalance may be responsible for the development and progression of RA. The combination of the treatment that manipulates key cytokines with the treatment that target Th17/Treg imbalance may lead to novel and effective immunotherapies for RA. Targeting of Th17/Treg balance can be done at different levels: cytokines, receptors, cells or signaling pathways. Some examples of targeting are described below, taking RA as an example where many
Conclusion
Th17 and Treg cells are both implicated in inflammatory and autoimmune diseases. Th17 cells are involved in the induction and propagation of pathologies whereas Treg cells inhibit autoimmunity and are responsible for tolerance against self-antigens. Th17 and Treg cells share common factors, such as TGF-β, that affect their development and generation. The balance between inflammation (Th17 cells) and tolerance (Treg cells) may influence pathology or disease outcomes in autoimmune diseases,
Conflict of interest
The author declares no financial or commercial conflict of interest.
Acknowledgments
Professor Miossec is a senior member of and supported by the Institut Universitaire de France. His laboratory is supported by grants from the OPERA IHU prometteur and the EU Marie Curie Network EUTRAIN. Melissa Noack is supported by the Institut Universitaire de France.
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