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Review
. 2022 Aug 12:13:974066.
doi: 10.3389/fimmu.2022.974066. eCollection 2022.

Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma

Weihang Luo  1   2 , Jindong Hu  1 , Weifang Xu  3 , Jingcheng Dong  1   2
Affiliations
Review

Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma

Weihang Luo et al. Front Immunol. .

Abstract

Immune response in the asthmatic respiratory tract is mainly driven by CD4+ T helper (Th) cells, represented by Th1, Th2, and Th17 cells, especially Th2 cells. Asthma is a heterogeneous and progressive disease, reflected by distinct phenotypes orchestrated by τh2 or non-Th2 (Th1 and Th17) immune responses at different stages of the disease course. Heterogeneous cytokine expression within the same Th effector state in response to changing conditions in vivo and interlineage relationship among CD4+ T cells shape the complex immune networks of the inflammatory airway, making it difficult to find one panacea for all asthmatics. Here, we review the role of three T helper subsets in the pathogenesis of asthma from different stages, highlighting timing is everything in the immune system. We also discuss the dynamic topography of Th subsets and pathogenetic memory Th cells in asthma.

Keywords: CD4+ memory T cell; T helper cells; Th1; Th17; Th2; asthma; cytokines; pathogenetic T cells.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
CD4+ T cells differentiation and heterogeneity in the context of asthma. The early differentiation is primed by antigen presentation of DCs in lymphoid tissue. Whether naïve T cell differentiates into Tfh or Teff cell is determined by TCR signal strength. When stimulated by a high TCR signal, naïve T cells differentiate into Teff cells. Concurrently, Innate cytokines direct functionally distinct effector programs (e.g., Th1, Th2, and Th17) by inducing lineage-defining transcriptional networks. Several phenotypically and functionally CD4+ T cells have recently been identified based on the expression of cytokines, transcription factors, or surface markers.
Figure 2
Figure 2
Mechanisms that condition inception of early-life asthma. IL-33 was spontaneously produced by epithelial cells until the age of three years, a period termed the alveolar phase of lung development. Under the influence of IL-33, DCs upregulate OX-40L and suppress IL-12p35, thus favoring Th2 cell skewing, and ILC2s were accumulated and activated in the lung. ILC2s provide IL-13 to boost DCs that recognize allergens to migrate into lymphoid tissue. DCs in lymphoid tissue promote Th2 differentiation with the help of IL-4 derived from basophils and simultaneously inhibit Th1 differentiation. IL-13 derived from Th2 induces AHR, which is a hallmark of recurrent wheeze in children who develop asthma.
Figure 3
Figure 3
The role of Th1, Th2, and Th17 cells in stable asthma. The eosinophils-recruiting chemokines CCL11 and CCL24 from the endothelial cell are induced by IL-4 and IL-13 from Th2 cells. IL-5 produced by Th2 cells then leads to the activation of eosinophils. Similarly, the neutrophil-attracting chemokines CXCL1, CXCL5, and CXCL8 by endothelial are induced by IL-17 from Th17 cells. Th17 cells could also directly chemoattract neutrophils via the release of CXCL8. The production of Amphiregulin and IL-13 is from Th2 cells. Amphiregulin acts on eosinophils to produce osteopontin which triggers airway fibrosis. IL-13 mainly drives goblet cell metaplasia and AHR. IL-17 produced by Th17 cells contributes to the AHR. IFN-γ effects on mast cells increase their ability to release histamine and IL-13, leading to AHR and goblet cell metaplasia.
Figure 4
Figure 4
The role of Th1, Th2, and Th17 cells in asthma exacerbation. Once encounter respiratory viruses and allergens, airway epithelial cells produce a wide range of cytokines as the first immune responders, most notably IL-33, IL-1β, IL-6, and CXCL8. Respiratory viral infections mostly elicit a Th1 immune response and less commonly trigger a Th17 immune response. TRM Th2 cells are first reactivated in the presence of IL-33 and cognate antigen. Subsequently, circulating memory Th2 cells are recruited to the lung. A similar scenario also occurs in virus-specific Th1 immune response. IL-1β and IL-6 promote Th17 cell differentiation and CXCL8 derived from Th17 cells and epithelial cells induce neutrophil recruitment to the lung.
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