Mechanisms underlying helper T-cell plasticity: implications for immune-mediated disease

Abstract

CD4 helper T cells are critical for proper immune cell homeostasis and host defense but are also major contributors to immune and inflammatory disease. Arising from a simple biphasic model of differentiation (ie, TH1 and TH2 cells). A bewildering number of fates seem possible for helper T cells. To what extent different helper cell subsets maintain their characteristic gene expression profiles or exhibit functional plasticity is a hotly debated topic. In this review we will discuss how the expression of "signature cytokines" and "master regulator" transcription factors do not neatly conform to a simple helper T-cell paradigm. Although this might seem confusing, the good news is that the newly recognized complexity fits better with our understanding of immunopathogenesis. Finally, we will discuss factors, including epigenetic regulation and metabolic alterations, that contribute to helper cell specificity and plasticity.

Fig 1. Helper T cells “Then” and “Now”

More than two decades ago, we viewed helper T cells as having two major fates, Th1 and Th2 cells. But now we recognize the new diversity of helper T cells including Th17, Th9, Th22, Tfh and different types of regulatory T cells.

Fig 2. Plasticity and Promiscuity in Helper T cells

Recent advances have allowed us to point out several evidences of plasticity of helper T cells. Helper T cells can express the signature cytokines (a) and the master regulators (b) outside of lineages. Moreover, helper T cells can alter their phenotypes by the environmental stimulations (c).

Fig 3. Mechanisms underlying plasticity of Helper T cells

(a) Specific modifications of the histone molecules that make up the nucleosomes are associated with accessibility. (b) Cytokine milieu can induce “pioneering factors” and activate different STATs, which are indispensable for establishing the genomic epigenetic landscapes of developing helper T cells and dictating the accessibility of key target genes. Master regulators may be better viewed as critical modulators, but not drivers of the chromatin architecture underlying helper cell identity. (c) Alterations in T cell metabolism also have critical roles in the plasticity of helper T cell lineages.