Recent advances in understanding the Th1/Th2 effector choice

Abstract

For over 35 years since Mosmann and Coffman proposed the seminal "type 1 T helper (Th1)/type 2 T helper (Th2)" hypothesis in 1986, the immunological community has appreciated that naïve CD4 T cells need to make important decisions upon their activation, namely to differentiate towards a Th1, Th2, Th17 (interleukin-17-producing T helper), follicular T helper (Tfh), or regulatory T cell (Treg) fate to orchestrate a variety of adaptive immune responses. The major molecular underpinnings of the Th1/Th2 effector fate choice had been initially characterized using excellent reductionist in vitro culture systems, through which the transcription factors T-bet and GATA3 were identified as the master regulators for the differentiation of Th1 and Th2 cells, respectively. However, Th1/Th2 cell differentiation and their cellular heterogeneity are usually determined by a combinatorial expression of multiple transcription factors, particularly in vivo, where dendritic cell (DC) and innate lymphoid cell (ILC) subsets can also influence T helper lineage choices. In addition, inflammatory cytokines that are capable of inducing Th17 cell differentiation are also found to be induced during typical Th1- or Th2-related immune responses, resulting in an alternative differentiation pathway, transiting from a Th17 cell phenotype towards Th1 or Th2 cells. In this review, we will discuss the recent advances in the field, focusing on some new players in the transcriptional network, contributions of DCs and ILCs, and alternative differentiation pathways towards understanding the Th1/Th2 effector choice in vivo.

Keywords: Th1/Th2 effector choice; dendritic cells; innate lymphoid cells.

Figure 1.. Contributions of dendritic cell subsets in the initiation of classical and alternative differentiation pathways for the generation of Th1 and Th2 cells in vivo.

Presented here is our updated view of the Th1/Th2 T effector decision in vivo. In response to an in situ immunological insult, local antigen-presenting dendritic cells acquire Ag and home to the nearest draining lymph node to present Ags. In the case of a pro-Th1 insult, such as a bacterial infection, bacterial Ag-laden dendritic cells can present bacterial Ags to naïve T cells and produce IL-12 in order to help generate bacterial Ag-specific Th1 cells (A). In parallel, some bacterial PAMPs can trigger Ag-laden dendritic cells to produce pro-Th17 cytokines, including IL-1β, IL-6, and TGFβ (B). Bacterial Ag-specific Th17 cells can subsequently respond to IL-12 and/or IL-23 in order to generate T-bet⁺ Th1-like Th17 cells (C) and ex-Th17-Th1-like cells (D) via unclear mechanisms. In contrast to a pro-Th1 insult, allergen exposure or a helminth infection is able to elicit a Th2 Ag-specific T cell response. In this scenario, helminth- or allergen-Ag-bearing dendritic cells home to the nearest draining lymph node, where they may select for Ag-specific naïve T cells to generate an Ag-specific Th2 cell response (E). In parallel, some helminth- or allergen-Ag-laden dendritic cells may instead help to generate Th17 cells, which may subsequently give rise to GATA3⁺ Th2-like Th17 cells (F) and ex-Th17-Th2-like cells (G). Ag, antigen; cDC, conventional dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; PAMP, pathogen-associated molecular pattern; TGFβ, transforming growth factor beta; Th1, type 1 T helper; Th2, type 2 T helper; Th17, interleukin-17-producing T helper; TNF, tumor necrosis factor.

Figure 2.. An updated view of the players in situ that help to shape a Th1/Th2 response.

Presented here is our updated view of the Th1/Th2 T effector decision in situ/in vivo. In response to an immunological insult in a complex tissue, such as the lung, local innate immune cells respond appropriately to guide the downstream selection of Th1 or Th2 cells. In response to a pro-Th1 bacterial infection (A–C), in situ NK cells and ILC1s respond to alarmins to produce IFNγ and local dendritic cells acquire bacterial Ags (A). Ag-laden dendritic cells may then travel to the nearest dLN to present bacterial Ags and generate bacterial Ag-specific Th1 cell or a mixed Th17 and Th1 cell response. Bacterial Ag-specific Th1, Th17, T-bet⁺ Th1-like Th17, and ex-Th17-Th1-like cells can then home back to the site of infection or Th17 cells can generate T-bet⁺ Th1-like Th17/ex-Th17-Th1-like cells in situ (B) in order to coordinate with local NK cells, ILC1 cells, and macrophages to control the bacterial infection (C). The potential antagonistic effects between Th1 cells and lung-resident ILC2s in this context are unclear. In contrast to a pro-Th1 insult, allergen exposure or a helminth infection is able to elicit a Th2 Ag-specific cell response (D–F). In this scenario, a helminth infection is sufficient to drive the production of alarmins (IL-33/IL-25) from the lung epithelium and activate local tissue ILC2s (D). In situ ILC2s can produce IL-4/IL-13 in response and promote helminth Ag-bearing dendritic cells homing to the nearest dLN. Helminth Ag-specific naïve T cells are selected by the Ag-laden dendritic cell and helminth Ag-specific Th2 or a mixture of Th17 and Th2 cells are generated (E). Helminth Ag-specific Th2, Th17, Th2-like Th17 cells, and ex-Th17-Th2-like cells may then home back to the infected tissue in order to work in conjunction with locally recruited and activated eosinophils, B cells, and ILC2s in order to expel or kill the invading helminth (F). Ag, antigen; dLN, draining lymph node; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; NK, natural killer; Th2, type 2 T helper; Th17, interleukin-17-producing T helper; TNF, tumor necrosis factor.