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.

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

“…Th1 cells produce IFN-γ and express the master transcription factor T-bet. 192 Th1-cell development is dependent on IL-12mediated STAT4 activation. In contrast, Th2 cells express high levels of the transcription factor GATA3 and produce cytokines IL-4, IL-5, and IL- 13.…”

“…192 Th17 cells, which are defined by the expression of the master transcription factor RORγt, can be generated in the presence of TGF-β and IL-6. 192 The analysis of mTOR-deficient CD4 + T cells demonstrates that mTOR signaling is critical for Th1-, Th2-, and Th17cell differentiation. 187 Further analysis of CD4 + T cells lacking RHEB shows impairment of Th1-cell differentiation without a substantial effect on Th2-cell differentiation, associated with reduced STAT4 phosphorylation in response to IL-12 158 or through control of T-bet phosphorylation.…”

Identification and Regulation of Interleukin-17 (IL-17) Family Ligands in the Teleost Fish European Sea Bass

“…Upon activation, naïve Th cells differentiate into different subtypes. The main and classical types were Th1 cells, which produce interferon gamma (IFNγ), interleukin (IL)-2, and tumor necrosis factor-α (TNFα), and are important for antiviral and antibacterial cellular immunity, whereas Th2 cells produce IL-4, IL-5, and IL-13, which trigger the humoral immune response and are important against extracellular pathogens [3]. Although other Th populations have been described during the last two decades in mammals, including follicular helper T cells (Tfh), induced T-regulatory cells (iTreg), the regulatory type 1 cells (Tr1), or the potentially distinct T-helper 9 (Th9), the Th17 cell subpopulation received particular attention.…”

“…Th17 cells are activated by IL-23 and secrete IL-17A, IL-17F, IL-21, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokines [4]. Mammalian IL-17 is a cytokine family that comprises six ligands, from A to F. IL-17A and IL-17F ligands, mainly produced by Th17 cells and used as their hallmark, are considered pivotal proinflammatory cytokines in autoimmune disorders and in the immunological response towards pathogens, playing a special role in the regulation of the gut microbiota and hence in the first line of defense in the mucosal tissues [3]. However, other lymphocyte subtypes, such as CD8 + T cytotoxic, natural killer T (NKT), γδT, or innate lymphoid cells, also produce IL-17A and F cytokines [5].…”

In vitro-generated alloantigen-specific Th9 cells mediate antileukemia cytotoxicity in the absence of graft-versus-host disease

“…Therefore, one major challenge in BMT is the identification of T-cell subsets provoking antitumor cytotoxicity without causing GVHD. T helper (Th) subsets are programmed into various lineages dependent on ligand interactions and the cytokine milieu [1]. Th9 cells, which can be generated from naïve CD4 cells after activation in the presence of IL-4 and TGF-β are characterized by increased secretion of IL-9 and have been proven to exhibit efficient antitumor capacity especially toward melanomas [2][3][4].…”