Life is about change and instability–so should we be surprised that our favorite T-cell lineages are not as stable as we desperately hoped they would be? Probably not, and as much as this complicates our scientific lives, we need to understand this and learn to interpret our data accordingly, no matter how little we like it. But let’s start at the beginning. In the mid 1980s Mosmann et al. made the fundamental observation that T-helper (Th) cells could be distinguished into two subsets with fundamentally different functional properties: Th1 cells, which produce IFN-γ, granulocyte macrophagecolony stimulating factor (GM-CSF) and IL-2, and Th2 cells, which produce IL-4 [1]. Shortly thereafter, the concept evolved that IFN-γ-producing Th1 cells are the cells that promote pathology in a number of autoimmune diseases, including autoimmune Type 1 diabetes and multiple sclerosis, and that Th2 cells are ‘good’and provide protection, or at least, are neutral [2–4]. Not surprisingly, however, evidence soon appeared suggesting that Th2 cells had pathogenic potential in some autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE) and autoimmune gastritis [5, 6]. However, even before that realization the discussion had begun as to how stable T-cell lineages are [7–9]. The dawn of the 21st century brought with it the rise of the Th17 cell. Cua and colleagues first showed that IL-23 was indispensable for induction of EAE [10], and then IL-23-promoted IL-17-producing cells and Th17 cells were established as a Th1/Th2-independent T-cell lineage [11, 12]. Subsequently, a number of papers established Th17 cells as being critical for tissue inflammation in animal models of rheumatoid arthritis and EAE [11, 13].

However, the debate continued as to which cytokines were the true harbingers of disease pathology. For example, IFN-γ was shown to be important for disease pathology, but so was TNF, IL-17 and IL-23 [10, 11, 14]. Shortly thereafter, it was questioned whether the signature Th17 cytokines, IL-17A and IL-17F, were as critical for the pathogenesis of autoimmune diseases as initially thought, since deficiency of GM-CSF, a cytokine that these cells also produce, completely abolished disease, whereas genetic deficiency of Th17 signature cytokines did not [15–17]. Interestingly, GM-CSF had been reported to be critical for EAE almost a decade earlier [18]. Thus, why was IL-23 critical for disease, but not other Th17 signature cytokines? As it turned out, IL-23 is linked to the production of GM-CSF by Th17 cells [19]. Since the initial description of Th17 cells, additional T-cell lineages have emerged, each with a particular role in immunity and autoimmune disease pathology: Tregs, follicular helper T (Tfh) cells, and most recently, Th9 and Th22 cells [3]. To make matters more complicated, the different T-cell lineages may not be as stable as we would like to assume, and they can change their phenotype (cytokine secretion, transcription factor [TF] and surface receptor expression) in response to different environmental stimuli [20]. Furthermore, T cells can affect each other’s differentiation, viability and stability and their role in immunity (ie, their function in disease). Interestingly, it appears that highly proinflammatory Th17 cells may go hand-in-hand with anti-inflammatory Tregs [20].