Helper T cell differentiation

Abstract

CD4⁺ T helper cells are key regulators of host health and disease. In the original model, specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcriptional programs, but recent studies have revealed increasing complexities for CD4⁺ T-cell differentiation. Here, we first discuss CD4⁺ T-cell differentiation from a historical perspective by highlighting the major studies that defined the distinct subsets of T helper cells. We next describe the mechanisms underlying CD4⁺ T-cell differentiation, including cytokine-induced signaling and transcriptional networks. We then review current and emerging topics of differentiation, including the plasticity and heterogeneity of T cells, the tissue-specific effects, and the influence of cellular metabolism on cell fate decisions. Importantly, recent advances in cutting-edge approaches, especially systems biology tools, have contributed to new concepts and mechanisms underlying T-cell differentiation and will likely continue to advance this important research area of adaptive immunity.

Keywords: T cells; Treg; differentiation; immunometabolism; plasticity.

Fig. 1

Timeline of major T helper cell discoveries. T helper populations (top) and major transcriptional regulators (bottom) listed in chronological order of the first published observation and/or the commonly agreed upon period establishing a separate lineage

Fig. 2

Transcriptional regulators of T helper cells. T helper cell subsets and associated positive (green) and negative (red) transcriptional regulators are separated by master regulators (top), signaling transducer and activator of transcription (STAT) molecules (middle), and additional important transcription factors (bottom)

Fig. 3

T helper cell plasticity and heterogeneity. a Representative diagram of plasticity in selected T helper cells. Differentiated T helper cells can coexpress master transcriptional regulators from other lineages. b Diagram with example tSNE (T-distributed stochastic neighbor embedding) plot generated from single-cell RNA-sequencing (scRNA-seq) data. Single-cell analysis allows for the discovery of subpopulations with unique expression profiles

Fig. 4

Metabolic control of T helper cell differentiation. Activated T cells undergo metabolic reprogramming, which leads to permissive epigenetic alterations of T effector genes. Much of this pathway is coordinated by mammalian target of rapamycin (mTOR) signaling and mitochondrial function to generate metabolic co-factors of epigenetic-modifying enzymes