Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells

Abstract

CD4+ T cells are critical for host defense but are also major drivers of immune-mediated disease. These T cells specialize to become distinct subsets and produce restricted patterns of cytokines, which are tailored to combat various microbial pathogens. Although classically viewed as distinct lineages, recent work calls into question whether helper CD4+ T cell subsets are more appropriately viewed as terminally differentiated cells or works in progress. Herein, we review recent advances that pertain to this topic and the mechanisms that contribute to helper CD4+ T cell commitment and plasticity. The therapeutic implications of these new findings are also considered.

Fig. 1

The Classical Monolithic View of Helper T Cell Differentiation: Lineages and Master Regulators. Initial studies arising from in vitro cultured Thelper1 (Th1) and Th2 cells led to the idea that these subsets behaved like lineages, meaning their phenotype (i.e. selective cytokine production) was inflexible. Accordingly, these subsets expressed lineage-defining transcription factors that were sufficient to impart this selective cytokine production. As newer subsets of cytokine producing cells were identified, they too were viewed as stable lineages.

Fig. 2

Flexibility and Plasticity of Helper T cells. Recent studies of Th cells have revealed more flexibility in cytokine production than predicted by earlier work and there are now many examples of plasticity of Th cell phenotype. CD4⁺ T cells can change their profile of cytokine production (dotted lines) and there are now circumstances in which the expression of master regulators is transient or instances where cells express more than one master regulator. New subsets are also recognized such as Th9 and Th22 cells, which selectively produce IL-9 and IL-22 respectively.

Fig. 3

A More Nuanced View of Th Differentiation and Regulated Expression of Transcription Factors. Recent insights suggest that it is probably more appropriate to view the process of Th cell differentiation in the context of varying ratios of transcription factors, whose expression is regulated by an array extrinsic and intrinsic factors. That is, some factors like GATA3 and Rorγt have roles in thymic T cell development, but in some subsets, the expression of these factors is further induced (Th2 and Th17 respectively), whereas in other subsets (e.g. Th1 cells), expression declines. Foxp3 is highly expressed in T reg cells, but it now appears that it can be expressed more widely in T cells in which its expression is transient. Rorγt and Foxp3 can be expressed in the same cells and associate with one another. Other Foxp3+ Tregs express T-bet, which seems to be important for the proper trafficking to sites of inflammation. Th17 cells, which express Rorγt, can also express T-bet and acquire the ability to make IFN-γ. Follicular helper T cells express the transcriptional repressor Bcl6. Tfh can arise independently from other subsets, can also be generated from other T helpers or can even develop to preferentially express cytokines typically expressed by helper cell subsets. Cytokines that drive helper cell differentiation induce expression of these different transcription factors, but in addition epigenetic factors also influence expression. However, the epigenetic modifications of the genes encoding T-bet and GATA3 suggest that they are “poised” for expression. In addition, microRNAs and another factor that can tune gene expression in helper cell subsets. Thus, the bottomline is that transcription factor expression is more dynamic and fluid than originally recognized. Not surprisingly, the cytokines regulated by these factors also seem to have more plasticity in their regulation. Although, a few transcription factors are shown, this is undoubtedly a vast oversimplification and likely a panoply of the factors contribute to the specialized function of T cells.