ReviewThe plasticity of human Treg and Th17 cells and its role in autoimmunity
Introduction
CD4+ T helper (Th) cells are an essential element of the adaptive immune system, regulating B cell dependent, humoral as well as CD8+ cytotoxic T cell dependent cellular immune responses. Moreover, CD4+ T cells are able to interact with the innate immune system and respond to stimuli in particular from dendritic cells (DC). Upon peptide/MHC-class II TCR mediated antigen encounter, naive CD4+ T cells are activated and differentiate into T effector cells, which can generate long lasting memory T cells. Depending on the antigen and strength of stimulation, cytokine milieu, co-stimulatory and various additional factors, CD4+ T cells can differentiate into distinct subpopulations with specialized functions [1], [2].
Classically, CD4+ T cells were divided into Th1 and Th2 subsets. Th1 cells produce the signature cytokine interferon (IFN)-γ and are induced in the presence of interleukin (IL)-12. They express the specific transcription factor Tbet (TBX21) and are generated in response to viral infections where they provide help to CD8+ T cells. Th2 cells are primarily linked to humoral immune responses by providing B cell help and are induced in the presence of IL-4. Th2 cells express the transcription factor GATA3 and are characterized by the expression of the signature cytokines IL-4, IL-5, and IL-13. However, since the discovery of Th1 and Th2 cells, several additional Th cell subpopulations have been described. So far, the most prominent additions are the FoxP3+ regulatory T cells (Treg) and IL-17 producing Th17 cells. Regulatory T cells are a distinct lineage of CD4+ T cells, generated during thymic development, which play an important role in maintaining peripheral tolerance. While Th17 cells are induced in the presence of transforming growth factor (TGF)-beta and IL-21, IL-6 or IL-1β and play a major role in fighting extracellular pathogens. Importantly, both of the latter populations are believed to play a major role in human autoimmune diseases [1], [3].
Although CD4+ Th cell polarization based on the Th1/Th2 paradigm was believed to be a stable process with low grade of variability, recent data provided evidence that this is not the case for many Th subpopulations. Indeed, under certain circumstances most of the differentiated Th cells and in particular Th17 and Treg cells show a great magnitude of plasticity and are able to change their phenotype and function. In this review we discuss the recent findings about Th cell plasticity with an emphasis on Treg and Th17 cells and their role in the human autoimmune disease MS.
Section snippets
Th17 cells
It is now established that Th17 cells represent, in addition to Th1 and Th2 cells, an independent helper T cell lineage [4], [5]. Th17 cells were initially described based on their secretion of IL-17. They express a series of other cytokines including IL-17F, IL-21, GM-CSF and IL-22 [1]. Their lineage specific transcription factor is the retinoic acid receptor-related orphan receptor γt (RORγt, in humans RORc), which controls development and function of Th17 cells [6]. However, RORγt acts in
Th17 plasticity
It was noted from early on that at least a subset of Th17 cells had the potential to secrete IFN-γ in mice and humans and thus identify a population with Th1-like features [2]. This was surprising, since initial studies have found that IFN-γ can block Th17 development [107]. By using reporter mice for IL-17F this phenomenon was studied in more detail in vitro and in vivo. It was found that the Th17 stability is dependent on TGF-β but is lost in the presence of IL-12, favoring the expression of
Concluding remarks
The plasticity of CD4+ T cells and in particular of Tregs and Th17 cells might have evolved to keep elasticity in combination with stability to enable the immune system to most flexibly deal with pathogens and changes in the environment. However, this flexibility also comprises a potential threat to the host, since the deregulation of this system enhances the risk of developing autoimmunity. It is therefore not surprising that several mechanisms have evolved to control T cell plasticity and
Conflict of interest
The authors declare no competing financial interests.
Acknowledgments
This work was supported by a National MS Society Collaborative Research Center Award CA1061-A-18, National Institutes of Health Grants P01 AI045757, U19 AI046130, U19 AI070352, and P01 AI039671, and by a Jacob Javits Merit award (NS2427) from the National Institute of Neurological Disorders and Stroke, the Penates Foundation and the Nancy Taylor Foundation for Chronic Diseases, Inc. (to D.A.H.). The authors would like to thank S. Ni Choileain for critical reading of the manuscript.
References (150)
- et al.
Regulatory T cells and immune tolerance
Cell
(2008) - et al.
The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells
Cell
(2006) - et al.
Th17: the third member of the effector T cell trilogy
Current Opinion in Immunology
(2007) - et al.
T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma
Immunity
(2008) - et al.
Critical regulation of early Th17 cell differentiation by interleukin-1 signaling
Immunity
(2009) - et al.
A validated regulatory network for Th17 cell specification
Cell
(2012) - et al.
CD49d provides access to “untouched” human Foxp3+ Treg free of contaminating effector cells
Blood
(2009) - et al.
Induction of intestinal Th17 cells by segmented filamentous bacteria
Cell
(2009) - et al.
Regulation of epithelial immunity by IL-17 family cytokines
Trends in Immunology
(2012) - et al.
The biological functions of T helper 17 cell effector cytokines in inflammation
Immunity
(2008)
Functional specialization of interleukin-17 family members
Immunity
Myelin proteolipid protein: an effective autoantigen and target of autoimmunity in multiple sclerosis
Journal of Autoimmunity
Increased memory Th17 cells in patients with neuromyelitis optica and multiple sclerosis
Journal of Neuroimmunology
IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease
Trends in Immunology
Th17 and regulatory T cells in mediating and restraining inflammation
Cell
Development and maintenance of regulatory T cells
Immunity
Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other
Trends in Immunology
CCR6 expression defines regulatory effector/memory-like cells within the CD25(+)CD4+ T-cell subset
Blood
Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression
Blood
Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death
Blood
CD147 (Basigin/Emmprin) identifies FoxP3+CD45RO+CTLA4+-activated human regulatory T cells
Blood
Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery
Immunity
Homing to suppress: address codes for Treg migration
Trends in Immunology
Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease
Lancet
A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease
Mucosal Immunology
IL-17 and Th17 cells
Annual Review of Immunology
Helper T-cell identity and evolution of differential transcriptomes and epigenomes
Immunological Reviews
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17
Nature Immunology
Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages
Nature Immunology
TH17 cells in development: an updated view of their molecular identity and genetic programming
Nature Reviews Immunology
The AP-1 transcription factor Batf controls T(H)17 differentiation
Nature
IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype
Proceedings of the National Academy of Sciences of the United States of America
Induction and effector functions of T(H)17 cells
Nature
Development, cytokine profile and function of human interleukin 17-producing helper T cells
Nature Immunology
Interleukins 1[beta] and 6 but not transforming growth factor-[beta] are essential for the differentiation of interleukin 17-producing human T helper cells
Nature Immunology
IL-21 and TGF-beta are required for differentiation of human T(H)17 cells
Nature
Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain
Nature
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
Journal of Experimental Medicine
Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells
Nature Immunology
Phenotypic and functional features of human Th17 cells
Journal of Experimental Medicine
Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model
Journal of Experimental Medicine
The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation
International Immunology
Phenotypical characterization of human Th17 cells unambiguously identified by surface IL-17A expression
Journal of Immunology
Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis
Current Opinion in Allergy and Clinical Immunology
Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome
Nature
Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3
Journal of Experimental Medicine
Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis
Journal of Experimental Medicine
STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis
New England Journal of Medicine
Multiple sclerosis
Journal of Clinical Investigation
Increased frequencies of myelin oligodendrocyte glycoprotein/MHC class II-binding CD4 cells in patients with multiple sclerosis
Journal of Immunology
Cited by (303)
Purification and identification of anti-inflammatory peptides from sturgeon (Acipenser schrenckii) cartilage
2023, Food Science and Human WellnessSodium perturbs mitochondrial respiration and induces dysfunctional Tregs
2023, Cell MetabolismImmuno-metabolic control of the balance between Th17-polarized and regulatory T-cells during HIV infection
2023, Cytokine and Growth Factor Reviews