Plasticity and lineage commitment of individual TH1 cells are determined by stable T-bet expression quantities

Abstract

T helper 1 (T_H1) cell identity is defined by the expression of the lineage-specifying transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated T_H1 cells based on their quantitative expression of T-bet and interferon-γ. Heterogeneous T-bet expression states were regulated by virus-induced type I interferons and were stably maintained even after secondary viral infection. Exposed to alternative differentiation signals, the sorted subpopulations exhibited graded levels of plasticity, particularly toward the T_H2 lineage: T-bet quantities were inversely correlated with the ability to express the T_H2 lineage-specifying transcription factor GATA-3 and T_H2 cytokines. Reprogramed T_H1 cells acquired graded mixed T_H1 + T_H2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated T_H1 cells was essential to ensure T_H1 cell stability. Thus, innate cytokine signals regulate T_H1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges.