T helper 1 cells and interferon gamma regulate allergic airway inflammation and mucus production - PubMed (original) (raw)

T helper 1 cells and interferon gamma regulate allergic airway inflammation and mucus production

L Cohn et al. J Exp Med. 1999.

Abstract

CD4 T helper (Th) type 1 and Th2 cells have been identified in the airways of asthmatic patients. Th2 cells are believed to contribute to pathogenesis of the disease, but the role of Th1 cells is not well defined. In a mouse model, we previously reported that transferred T cell receptor-transgenic Th2 cells activated in the respiratory tract led to airway inflammation with many of the pathologic features of asthma, including airway eosinophilia and mucus production. Th1 cells caused inflammation with none of the pathology associated with asthma. In this report, we investigate the role of Th1 cells in regulating airway inflammation. When Th1 and Th2 cells are transferred together into recipient mice, there is a marked reduction in airway eosinophilia and mucus staining. To address the precise role of Th1 cells, we asked (i), Are Th2-induced responses inhibited by interferon (IFN)-gamma? and (ii) Can Th1 cells induce eosinophilia and mucus in the absence of IFN-gamma? In IFN-gamma receptor(-/-) recipient mice exposed to inhaled antigen, the inhibitory effects of Th1 cells on both airway eosinophilia and mucus production were abolished. In the absence of IFN-gamma receptor signaling, Th1 cells induced mucus but not eosinophilia. Thus, we have identified new regulatory pathways for mucus production; mucus can be induced by Th2 and non-Th2 inflammatory responses in the lung, both of which are inhibited by IFN-gamma. The blockade of eosinophilia and mucus production by IFN-gamma likely occurs through different inhibitory pathways that are activated downstream of Th2 cytokine secretion and require IFN-gamma signaling in tissue of recipient mice.

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Figures

Figure 4

Figure 4

Cytokine levels in BAL fluid after inhaled antigen exposure. After transfer of Th1, Th2, or Th1 + Th2 (2.5 × 106 cells from each population) and exposure to inhaled antigen, BAL fluid was collected and cytokines were measured by ELISA. The mean cytokine level (±SEM) is shown (n = 3 mice per group).

Figure 1

Figure 1

Cytokine production by Th1 or Th2 cells. At the time of transfer into recipient mice, in vitro–generated DO11.10 CD4 Th1 or Th2 cells were cultured with APCs in the presence of pOVA323–339. Supernatants were collected after 48 h, and cytokine ELISAs were performed. One experiment is shown and is representative of five experiments.

Figure 2

Figure 2

Effects of Th1 cells on airway eosinophilia. Th1, Th2, or Th1 + Th2 cells (numbers shown) were transferred into BALB/c recipient mice, and mice were exposed to inhaled OVA for 7 d. 24 h later, mice were killed and BAL was performed. Total cell and differential counts were performed on cells recovered from BAL in individual mice. Data represents mean number of BAL eosinophils (±SEM) (n = 4 mice per group). One experiment is shown and is representative of four experiments. Statistical significance was determined by unpaired Student's t test. *P < 0.05 Th2 versus Th1 (1.25) + Th2 (2.5); ‡ P < 0.002 Th2 versus Th1 (2.5) + Th2 (2.5).

Figure 3

Figure 3

Effects of Th1 cells on airway mucus production. Th1, Th2, or Th1 + Th2 cells (numbers shown) were transferred into BALB/c recipient mice, and mice were exposed to inhaled OVA for 7 d. 24 h later, mice were killed. Mucus staining was assessed on PAS-stained lung sections. Data represents mean HMI (±SEM) (n = 4 mice per group). One experiment is shown and is representative of four experiments. Statistical significance was determined by unpaired Student's t test. *P < 0.05 Th2 versus Th1 (2.5) + Th2 (2.5). ‡ P < 0.0004 Th2 versus Th1 (1.0) + Th2 (1.0) or Th1 (2.0) + Th2 (1.0).

Figure 5

Figure 5

Airway eosinophilia induced in IFN-γR−/− mice. Th1, Th2, or Th1 + Th2 cells (2.5 × 106 cells from each population) were transferred into IFN-γR+/+ (BALB/c) or IFN-γR−/− recipient mice, and mice were exposed to inhaled OVA. Total cell and differential counts were performed on cells recovered from BAL in individual mice. Data represents mean number of BAL eosinophils (±SEM) (n = 4 mice per group). One experiment is shown and is representative of two experiments. Statistical significance was determined by unpaired Student's t test. *P < 0.0001 Th2 versus Th1 + Th2.

Figure 6

Figure 6

Airway mucus production in IFN-γR−/− mice. Th1, Th2, or Th1 + Th2 cells (2.5 × 106 cells from each population) were transferred into IFN-γR+/+ (BALB/c) or IFN-γR−/− recipient mice, and mice were exposed to inhaled OVA. Mucus staining was assessed on PAS-stained lung sections. Data represents mean HMI (±SEM) (n = 4 mice per group). One experiment is shown and is representative of two experiments. Statistical significance was determined by unpaired Student's t test. *P < 0.0004 Th2 versus Th1 + Th2.

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