T Helper Cell Differentiation, Heterogeneity, and Plasticity

Abstract

Naïve CD4 T cells, on activation, differentiate into distinct T helper (Th) subsets that produce lineage-specific cytokines. By producing unique sets of cytokines, effector Th subsets play critical roles in orchestrating immune responses to a variety of infections and are involved in the pathogenesis of many inflammatory diseases including autoimmunity, allergy, and asthma. The differentiation of Th cells relies on the strength of T-cell receptor (TCR) signaling and signals triggered by polarizing cytokines that activate and/or up-regulate particular transcription factors. Several lineage-specific master transcription factors dictate Th cell fates and functions. Although these master regulators cross-regulate each other, their expression can be dynamic. Sometimes, they are even coexpressed, resulting in massive Th-cell heterogeneity and plasticity. Similar regulation mediated by these master regulators is also found in innate lymphoid cells (ILCs) that are innate counterparts of Th cells.

Figure 1.

Combinatorial expression of master transcription factors determines the heterogeneity and functionality of effector T helper (Th) cells, follicular Th (Tfh) cells, regulatory T (Treg) cells, and innate lymphoid cell (ILC) subsets. T-bet, GATA3, and RORγt are the master transcription factors of distinct Th cell and ILC subsets. Within the Th effector compartment, T-bet/RORγt coexpressing cells have been found under inflammation conditions. These cells could be derived from either T-bet- or RORγt-single positive cells. During type 2 immune responses, GATA3/T-bet coexpressing cells are also found. Similarly, in the ILC compartment, NKp46⁺ ILC3s coexpress T-bet and RORγt. Bcl6 is the master regulator for Tfh cells. Subsets of Tfh cells may either express low levels of effector master regulators, T-bet, GATA3, or RORγt, or have expressed one of these factors during their development. Interestingly, all of these master regulators, T-bet, GATA3, RORγt, and Bcl6, can be expressed by subsets of Foxp3-expressing Treg cells albeit at lower levels. Furthermore, although it is not indicated in the figure, all of these lymphocytes can express GATA3 but at various levels.