Atopic dermatitis (AD) is one of the most common inflammatory diseases, affecting up to 13 million children in the United States alone in 2009.1 The economic impact of AD is substantial, with an estimated annual cost to the US economy as high as $3.8 billion.2 Severe pruritus and cutaneous infections contribute to the morbidity of AD.3,4 Despite the above factors, the armamentarium of safe and effective systemic medical therapies for management of AD is limited, highlighting the need for improved understanding of pathogenic mechanisms.
This review will focus on the role of T-cells in AD. T helper (Th) cell development, diversity, and function and the impact of host-microbe interactions on T-cell development will be addressed. Evidence implicating specific Th subsets in AD will be presented. The relationship between altered host-microbe interactions and AD pathogenesis will then be discussed. Finally, insights garnered from the Stat6VT mouse model of AD will be reviewed.
T helper cell development and function
Distinct developmental programs initiated by specific cytokines, cytokine receptors, and transcription factors at the time of T-cell receptor engagement by antigen/MHC II complexes dictate T helper (Th) cell differentiation from naïve T cells.5 T helper cell subsets include Th1, Th2, Th9, Th17, Th22, Treg, and T follicular helper cells. Differentiation of Th2 cells will be reviewed as an example of Th cell lineage commitment. This will be followed by a summary of cytokines and transcription factors involved in differentiation of other Th subsets.
Differentiation of Th2 cells is promoted by IL-4-mediated activation of Janus kinases 1 and 3 with subsequent recruitment of Signal Transducer and Activator of Transcription 6 (STAT6), which becomes phosphorylated, dimerizes, and translocates to the nucleus inducing expression of Th2-specific target genes, including the master regulator of Th2 cell differentiation, GATA3.6,7 More recently, roles for STAT3 and STAT5 in Th2 cell differentiation were recognized.6,8 T helper 1 cell differentiation is stimulated by IL-12 and IFNγ and is mediated by STAT4 and T-bet. Development of Th9 cells is stimulated by TGFβ and IL-4 and requires STAT6, IRF4, and PU.1.8 Development of Th17 cells is stimulated by TGFβ and IL-6 or IL-21 and is mediated by STAT3 and RORγt. Inducible Treg cell development is stimulated by TGFβ and IL-2 and is mediated by STAT5 and FoxP3.6 The details of Th22 cell development and whether this is a distinct lineage have not as yet been determined.
Production of IFNγ by Th1 cells promotes cell-mediated immunity against intracellular pathogens.6 Production of IL-4, IL-5, and IL-13 by Th2 cells promotes immunity to extracellular parasites, as does the production of IL-9, IL-10, CCL17, and CCL22 by Th9 cells.8 The Th17 cell subset produces IL-17A, IL-17F, and IL-22 and mediate inflammatory responses to control extracellular bacterial and fungal infections. Host T-cell activity is modulated by Tregs through contact-dependant and independent pathways.8
Development of T-cells in mice is influenced by normal bacterial flora.9 The most defined example of this is for Th17 cell differentiation, which is markedly reduced in the intestinal lamina propria of gnotobiotic mice, and is restored upon oral gavage with conventional fecal flora.10,11 Importantly, segmented filamentous bacteria, a non-culturable species related to clostridia that colonizes the terminal ileum in many vertebrates, is sufficient to rescue defective Th17 cell development and promote Th1, Th2, and Treg development in the lamina propria of gnotobiotic mice.10,12 Other normal flora affect T-cell development as with Bacteroides fragilis-driven Th1 cell differentiation in the gut.13 Conversely, oral antibiotics can dramatically alter the composition of host intestinal bacterial flora, reducing the quantity of Th17 cells.11 Given that specific Th cell populations and host-microbe interactions are important for AD pathogenesis, it is conceivable that host-microbe interactions influence disease by regulating Th cell development and function in AD.
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