Review ArticleT cell subsets and their signature cytokines in autoimmune and inflammatory diseases
Introduction
T helper (Th) cells are characterized by different cytokine profiles which are used to define their subsets. However, it is still an area of debate if pathogenic Th cells can be defined by simple cytokine profiles.
Over a quarter of a century ago, Mossman and Coffman made the seminal observation that long-term Th clones could be distinguished based on their cytokine profiles, which afforded Th subsets different functional properties [1]: Th1 cells, characterized by the secretion of Interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF), and Th2 cells, which secrete interleukin (IL)-4, IL-5 and IL-13. This observation was novel and advanced the understanding of how the immune system adapts to specific pathogens and that Th subsets have unique roles in mediating protection. For example Th1 cells are responsible for cell-mediated immune responses, while Th2 are responsible for humoral-mediated immunity [2]. Interestingly, each of these Th subsets can promote immunopathology; for instance an excessive Th1 response will result in tissue damage, while excessive Th2 responses can result in atopy/hypersensitivity [2].
Since the discovery of the Th1/Th2 dichotomy, many additional Th subsets were discovered, each one with a unique cytokine profile, functional properties and presumed roles in autoimmune tissue pathology. These “new” Th subsets include IL-17 producing Th17 cells, regulatory Th cells (Tregs), and, recently, IL-9 producing Th9 cells and IL-22 producing Th22 cells. This article will review the different Th subsets in terms of cytokine profiles, how these cytokines influence and shape the immune response, and their relative roles in promoting pathology in autoimmune and inflammatory diseases. Furthermore, we will discuss whether Th cell pathogenicity can be defined solely based on their cytokine profiles and whether rigid definition of a Th cell subset by its cytokine profile is helpful.
Shown in Fig. 1 is an illustration of the pro-inflammatory and anti-inflammatory functions of the signature cytokines of each T cell subset.
Section snippets
Th1 cells
Th1 cells are the quintessential cell type involved in cell mediated inflammation and delayed-type hypersensitivity reactions. They are thought to be important for immunity to intracellular pathogens. Th1 cells are most often defined by their production of IL-2 and IFN-γ but have been reported to produce a number of cytokines including: TNF, lymphotoxin, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Committed Th1 effectors express the transcription factor T-bet. Factors
Th2 cells
Th2 cells are recognized for their role in host defense against multi-cellular parasites and their involvement in allergies and atopic illnesses. To a large extent, Th2 cells function in epithelial tissues, most notably the intestinal tract and lungs. Perhaps as a direct result, Th2 differentiation and function are intimately regulated by innate and epithelial cell types that inhabit these tissues [51]. Recent work has identified the actions of innate cytokines IL-25, IL-33 and thymic stromal
Th17 cells
The IL-17 family of cytokines comprises potent inflammatory mediators involved in host defense against extracellular bacteria, fungi and other eukaryotic pathogens. IL-17 cytokines have been implicated in a broad spectrum of inflammatory conditions and autoimmune diseases [103]. Currently, there are six known IL-17 family members: IL-17A (commonly referred to as IL-17), IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F [104]. Specialized CD4+ T helper cells (Th17) are the major source of IL-17 and
Th22 cells
Th22 cells are recent siblings of Th17 cells which produce predominantly the cytokine IL-22 and represent a separate Th subset with distinct gene expression and functions, and were initially associated with immunopathology of skin diseases [136], [137], [138]. IL-22 is a member of the IL-10 family of cytokines and it is produced by activated T cells, notably Th17 and Th22 cells, as well as by NK cells and γδ T cells, and it acts primarily on non-immune cells [139]. Recent evidence indicates
Th9 cells
IL-9 was first described as a T cell and mast cell growth factor and it is important in promoting mucus production and activation of mast cells as well as eosinophils [163]. It was initially viewed as a Th2 cell cytokine, however, more recently, IL-9 has been identified in a subset of T cells distinct from Th2 cells, now delineated as Th9 cells [164]. The development of Th9 cells requires the combination of TGF-β (which also promotes Tregs) and IL-4 (known to induce Th2 cells) [165].
Tregs
The concept of a specialized subset of T lymphocytes with suppressive function has been around since the early 1970s [172]. In the mid-1990s a novel subset of Th cells with “regulatory” function was identified and designated Tregs [173]. Tregs were later found to express the signature Foxp3 transcription factor, which is critical for their development, lineage commitment, and regulatory functions [174], [175]. Foxp3 expressing Treg subsets include thymically derived or natural Tregs (nTregs)
Discussion – or the enigma of the “Th1-like” Th17 cell
Here, we have summarized the most recent understanding of CD4+ Th cell subset “signature” cytokines in promoting autoimmune tissue pathology and/or mediating protection. Since a sustained and uncontrolled inflammatory response will be detrimental to the host, it must be self-limiting. As a result it seems that there is a switch point at which anti-inflammatory pathways are activated. Thus, instead of an elusive “pathogenic” T cell subset which secretes harmful cytokines, most Th cell subsets
Concluding remarks
The immune system seems to favor a balance between pathogenic and protective Th cells via dual roles for “subset-specific”, or “signature cytokines”, as well as allowing plasticity for subset differentiation and expression of “signature” cytokine(s) by other Th subsets. The observation that many Th subsets can convert into IFN-γ secreting Th1-like cells illustrates this fact since IFN-γ can be both pathogenic and protective. Targeting cytokines as therapy for autoimmune and/or inflammatory
Acknowledgments
This work was supported by Grants NS081237 (T.N.E.), NS52177 and G12MD007591 (T.G.F.) from the National Institute of Health, and Grants RG3499 and RG3701 from the National Multiple Sclerosis Society (T.G.F.) and a fellowship from the South Texas Center for Emerging Infectious Diseases at the University of Texas at San Antonio (I.R.).
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