The Role of T Cells and Macrophages in Asthma Pathogenesis: A New Perspective on Mutual Crosstalk

Abstract

Asthma is associated with innate and adaptive immunity mediated by immune cells. T cell or macrophage dysfunction plays a particularly significant role in asthma pathogenesis. Furthermore, crosstalk between them continuously transmits proinflammatory or anti-inflammatory signals, causing the immune cell activation or repression in the immune response. Consequently, the imbalanced immune microenvironment is the major cause of the exacerbation of asthma. Here, we discuss the role of T cells, macrophages, and their interactions in asthma pathogenesis.

Figure 1

Imbalance of T cells in asthma pathogenesis. In response to allergens, the naïve T (Tn) cells are activated by the macrophages and tend to differentiate into T helper (Th) 1, Th2, Th17, Th22, Th9, Th25, T regulatory (Treg), T follicular helper (Tfh), natural killer T (NKT), mucosal-associated invariant T (MAIT), γδT cells, cytotoxic CD8⁺T lymphocytes (CTLs), and memory T (Tm) cells. They secrete cytokines to activate and recruit the eosinophils, neutrophils, mast cells, and B cells. The arrows represent the secretions from these cells, affecting the progression of asthma. The transcriptional factors T-bet, Gata3, RAR-related orphan receptor (ROR) γt, Foxp3, and PU.1 are necessary to Th1, Th2, Th17, Treg, Th22, and Th9 cell activation. The signal transducer and activator of transcription (STAT) signals are involved in the process. Besides, caspase 8 and the Fas/FasL pathway are related to cell apoptosis mediated by CTLs.

Figure 2

Macrophage dysfunction in asthma pathogenesis. In response to allergens, macrophages differentiate into classically activated (M1) and alternatively activated (M2) macrophages. The arrows refer to the cytokines and chemokines secreted by macrophages, including tumor necrosis factor- (TNF-) α, interleukin (IL), and interferon- (IFN-) γ. M1 macrophages produce T helper (Th) 1-associated and Th17-associated cytokines, affecting the neutrophils. M2 macrophages further differentiate into M2a, M2b, and M2c macrophages, affecting the eosinophils.

Figure 3

Crosstalk between T cells and macrophages in asthma pathogenesis. The arrows represent the cytokines secreted by T cells and macrophages. Macrophages secrete interleukin- (IL-) 10 to repress T helper (Th) 2 and Th17 cells. Similarly, Treg cells secrete IL-10 to inhibit macrophages. Antigen-contained major histocompatibility complex (MHC) class I or II molecules on macrophages bind to the T cell receptor (TCR) on T cells to mediate the adaptive immune response. Extracellular vesicles (EVs) carrying miRNAs (miRNA-142, miRNA-126, miRNA-21, etc.) may be the modulators of the crosstalk between T cells and macrophages. In addition, the imbalance caused by the cytokine storm may be the main cause of severe asthma. The red side refers to the positive feedback loops while the blue side refers to the negative feedback loops.