Plasticity and lineage commitment of individual T H 1 cells are determined by stable T-bet expression quantities

Abstract

T helper 1 (T H 1) 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 H 1 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 H 2 lineage: T-bet quantities were inversely correlated with the ability to express the T H 2 lineage–specifying transcription factor GATA-3 and T H 2 cytokines. Reprogramed T H 1 cells acquired graded mixed T H 1 + T H 2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated T H 1 cells was essential to ensure T H 1 cell stability. Thus, innate cytokine signals regulate T H 1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges.