Helper T cell diversity and plasticity

Abstract

CD4(+) helper T cells play crucial roles for host defense and immune-mediated disease by their ability to differentiate into specialized subsets. These subsets attain restricted patterns of cytokine secretion and specific expression of master transcription factors in response to microbial pathogens. Classically, the various helper CD4(+) T cell subsets have been viewed as terminally differentiated lineages with limited flexibility. However, following the recognition of new subsets, there is increased recognition of plasticity. In this review, we highlight recent advances that pertain to this topic and the mechanisms that contribute to helper CD4(+) T cell differentiation and plasticity.

Figure 1

Flexibility and plasticity of helper T cells. Recent studies continue to reveal surprising flexibility in expression of “master regulator” transcription factors. In addition, there are now many examples in which helper T cell phenotypes can change their pattern of expression of signature cytokines and gene expression. Striking examples exist in which apparently fully committed “lineages” readily switch their phenotype, and there are now many circumstances where helper T cells have been shown to express more than one master regulator. This may be advantageous in terms of host defense, but needs to be borne in mind in thinking about effective therapies for immune-mediated disease and vaccine development.

Figure 2

Epigenetic status of lineage specific cytokine and transcription factor gene loci in helper T cell subsets. H3K4me3 (red flag) and H3K27me3 (blue flag) modifications on Ifng and Tbx21 loci in Th1, Th2 and Th17 cells are shown. Consistent with the selective expression of IFN-γ in Th1 cells, the Ifng gene displays H3K4me3 (permissive) marks in Th1 cells accompanied by H3K27me3 (repressive) marks in Th2 and Th17 cells. The Tbx21 gene is associated with permissive H3K4me3 marks in the absence of H3K27me3 marks in Th1 cells. Although, repressive H3K27me3 marks are present in Th2 and Th17 cells, H3K4me3 marks are also present. The Bcl6 gene is another example where accessible marks are maintained. Such bivalent epigenetic modifications on master regulator may functionally contribute to helper T cell plasticity. Thus, the epigenetic modifications provide explanations for elements of stability (e.g. cytokine genes) that coexist with modes of plasticity (e.g. master regulators genes) within the same subset of helper cells.