Plasticity within the αβ⁺CD4⁺ T-cell lineage: when, how and what for?

Abstract

Following thymic output, αβ⁺CD4⁺ T cells become activated in the periphery when they encounter peptide-major histocompatibility complex. A combination of cytokine and co-stimulatory signals instructs the differentiation of T cells into various lineages and subsequent expansion and contraction during an appropriate and protective immune response. Our understanding of the events leading to T-cell lineage commitment has been dominated by a single fate model describing the commitment of T cells to one of several helper (T(H)), follicular helper (T(FH)) or regulatory (T(REG)) phenotypes. Although a single lineage-committed and dedicated T cell may best execute a single function, the view of a single fate for T cells has recently been challenged. A relatively new paradigm in αβ⁺CD4⁺ T-cell biology indicates that T cells are much more flexible than previously appreciated, with the ability to change between helper phenotypes, between helper and follicular helper, or, most extremely, between helper and regulatory functions. In this review, we comprehensively summarize the recent literature identifying when T(H) or T(REG) cell plasticity occurs, provide potential mechanisms of plasticity and ask if T-cell plasticity is beneficial or detrimental to immunity.

Figure 1.

T-cell differentiation pathways. Following TCR ligation with appropriate co-stimulation, cytokines activate specific TFs and transcriptional regulators resulting in the differentiation of T cells into various identifiable states. For example IL-4 activates STAT-6 and GATA-3, initiating and repressing a suite of genes characteristic of T_H2 cells.

Figure 2.

T helper cell plasticity. Several studies have demonstrated the ability of cytokine-producing cells to change their cytokine-producing profile, under various conditions. In vitro generated (a) IL-17A-producing cells can upregulate IFNγ following re-polarization with IL-12, or following adoptive transfer into mice, as indicated. Similarly, cells that have previously activated an Il-17a programme in vivo (b) can upregulate IFNγ during EAE, as indicated. Whether other cytokine-producing cells display similar plasticity in vivo has not been conclusively demonstrated.

Figure 3.

T_REG specialization and plasticity. T_REG cells can co-express T helper cell lineage-defining TFs, such as Tbet and Foxp3 (red, lower right segment), during various infectious or inflammatory scenarios. This specialization appears to fine tune T_REG cells to more effectively regulate the corresponding effector T_H cell. For example Tbet⁺Foxp3⁺ T_REG cells can potently suppress Tbet⁺ T_H1 cells. Thus, the co-expression of various TFs is required to confer the appropriate and necessary regulatory programme. Whether these hybrid ‘specialized’ T_REG cells are intermediate cells in between the T_H to T_REG conversion (indicated by arrows in figure), or a stable population is unclear. GC, germinal centre.

Figure 4.

Potential mechanisms of T-cell plasticity. Various mechanisms of T-cell plasticity have been tested, suggested and loosely implied. Intrinsic mechanisms, (1) including the stage of T_H cell maturation may be inversely correlated to plasticity. (2) Post-transcriptional regulation by small RNA molecules, including miRNAs, can dramatically alter the T-cell phenotype. (3 and 4) Changing TF expression and activation with permissive epigenetic marks at TF binding sites can re-programme entire gene programmes. (5) A change in nutrient availability may trigger changes in intracellular metabolic pathways and the resultant T-cell phenotype and function. (6 and 7) Extracellular influences, including interactions with innate cell receptors or triggering of cytokine signalling pathways may dynamically alter cytokine receptor expression on T cells, making them permissive to subsequent re-programming signals. APC, antigen-presenting cell; Eos, eosinophil; ILC, innate-like helper cells; Mac, macrophage; Neut, neutrophil.