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. 2001 Apr 2;193(7):785-92.
doi: 10.1084/jem.193.7.785.

Inhibition of T1/ST2 during respiratory syncytial virus infection prevents T helper cell type 2 (Th2)- but not Th1-driven immunopathology

G Walzl  1 , S Matthews, S Kendall, J C Gutierrez-Ramos, A J Coyle, P J Openshaw, T Hussell
Affiliations

Inhibition of T1/ST2 during respiratory syncytial virus infection prevents T helper cell type 2 (Th2)- but not Th1-driven immunopathology

G Walzl et al. J Exp Med. .

Abstract

T cells secreting interleukin (IL)-4 and IL-5 (T helper cell type 2 [Th2] cells) play a detrimental role in a variety of diseases, but specific methods of regulating their activity remain elusive. T1/ST2 is a surface ligand of the IL-1 receptor family, expressed on Th2- but not on interferon (IFN)-gamma-producing Th1 cells. Prior exposure of BALB/c mice to the attachment (G) or fusion (F) protein of respiratory syncytial virus (RSV) increases illness severity during intranasal RSV challenge, due to Th2-driven lung eosinophilia and exuberant Th1-driven pulmonary infiltration, respectively. We used these polar models of viral illness to study the recruitment of T1/ST2 cells to the lung and to test the effects of anti-T1/ST2 treatment in vivo. T1/ST2 was present on a subset of CD4(+) cells from mice with eosinophilic lung disease. Monoclonal anti-T1/ST2 treatment reduced lung inflammation and the severity of illness in mice with Th2 (but not Th1) immunopathology. These results show that inhibition of T1/ST2 has a specific effect on virally induced Th2 responses and suggests that therapy targeted at this receptor might be of value in treating Th2-driven illness.

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Figures

Figure 1
Figure 1
T1/ST2+ cells are present in the lung during viral induced eosinophilia. Mice were scarified with Gvac and challenged intranasally with RSV 14 d later. T1/ST2+ cells were identified in BAL samples by indirect immunofluorescence. Cells were then blocked with rat Ig and stained with quantum red conjugated antibodies to CD4. Samples were analyzed on a Beckman Coulter EPICS Elite™ flow cytometer collecting data on at least 40,000 cells. A and B show T1/ST2+ cells in G/RSV mice at days 3 and 5 after intranasal RSV challenge. C and D show G/RSV mice treated with PBS (C) or IL-12 (D) at 4 d after intranasal RSV challenge. Representative plots for five mice per group are shown.
Figure 2
Figure 2
Anti-T1/ST2 treatment prevents RSV-induced weight loss during immune responses dominated by Th2-driven eosinophilia. Mice were primed with Gvac, Fvac, or β gal-vac and challenged with RSV intranasally 14 d later. Half of each group was given anti-T1/ST2 antibody daily from the day before intranasal RSV challenge (open symbols), whereas the other half was given isotype-matched irrelevant antibody (closed symbols). The percent weight loss or gain on subsequent days was calculated from the original weight of each individual mouse. The mean and standard deviation of five individual mice are shown (A). The data for β gal/RSV mice treated with anti-T1/ST2 is not shown for clarity, but weight loss was not significantly different from control treated β gal/RSV mice. In B, a separate experiment with just G/RSV-infected mice is shown. Each line represents an individual mouse treated with anti-T1/ST2 (dotted line) or irrelevant isotype-matched control (solid line).
Figure 3
Figure 3
Anti-T1/ST2 treatment reduces inflammation in the lung. G/RSV-infected mice were treated with rat Ig (closed symbols) or anti-T1/ST2 (open symbols), and cells from the airways were removed by BAL. Total viable cells were determined by trypan blue exclusion. Total lymphocytes were calculated by multiplying this number by the percent lymphocytes identified in forward and side scatter plots by flow cytometry (the position of lymphocytes being determined by expression of T and B cell markers). In the BAL, both total cell numbers (P = 0.02) and lymphocyte numbers (P = 0.03) were decreased in the anti-T1/ST2–treated group. (A). The percent of BAL eosinophils (B) was determined by differential counting in hematoxylin and eosin–stained cytocentrifuge preparations (identified by nuclear morphology and presence of eosinophilic granules). The data represents this percentage multiplied by the total viable cell count and is lower in the anti-T1/ST2 treated group (P = 0.005). The number of CD4+ and CD8+ T cells (C) is calculated by multiplying the percent of each subset (by flow cytometry) by the number of lymphocytes present. Both CD4+ (P = 0.02) and CD8+ T cells (P = 0.03) are fewer in anti-T1/ST2–treated mice. Each point represents an individual mouse from one of two independent experiments.
Figure 5
Figure 5
Anti-T1/ST2 treatment has no effect on the influx of cells into the lungs of mice primed with the fusion protein. Mice were scarified with Fvac and intranasally challenged with RSV 14 d later. Mice were treated with rat Ig or anti-T1/ST2 as shown. The number of total cells, lymphocytes, and CD4+ and CD8+ T cells was determined as described in Fig. 3. The results represent the mean and standard deviation of groups of five mice. Similar results were obtained in a separate experiment containing four mice per group.
Figure 4
Figure 4
Anti-T1/ST2 treatment reduces cytokine production in the lung. G/RSV-infected mice were treated with rat Ig control (solid bars) or anti-T1/ST2 (open bars). Lung lavage was performed 7 d after RSV challenge, and the cytokines in the BAL supernatant were assayed by ELISA. The results represent the mean and standard deviation of four mice per group and are representative of two independent experiments. Anti-T1/ST2 treatment decreases TNF (P = 0.04), IFN-γ (P = 0.029), and IL-5 (P = 0.04), but not IL-4.
Figure 6
Figure 6
Anti-T1/ST2 treatment slows the elimination of RSV from the lungs in eosinophilic mice. Mice were scarified with Fvac (diamonds) or Gvac (squares) and challenged with RSV 14 d later. At the time points shown, lungs were removed from rat Ig–treated (closed symbols) or anti-T1/ST2–treated (open symbols) mice. Homogenized lung was assessed for the presence of RSV by plaque assay on HEp-2 cells. The results represent the mean from four individual mice.
Figure 7
Figure 7
Anti-T1/ST2 treatment does not alter illness in IL-12–treated mice. Mice were scarified with Gvac on day 0 and treated with PBS (−) or IL-12 (+) from days −2 to +2. RSV was administered intranasally on day 14, and lung lavage was performed after a further 7 d. Total viable cells (A) were determined by trypan blue exclusion, and the percent eosinophilia (B) was determined by histological analysis of hematoxylin and eosin–stained cytocentrifuge preparations. Anti-T1/ST2 treatment decreased the percentage of eosinophils (P = 0.005), as did IL-12 treatment alone, but IL-12 treatment in conjunction with anti-T1/ST2 did not further decrease this percentage. Weight loss (C) was monitored throughout RSV challenge and represents the percentage of initial starting weight. Open symbols represent mice treated with anti-T1/ST2 antibody; closed symbols represent mice treated with rat Ig. Circles represent IL-12–treated mice; PBS control mice are represented by squares. The mean and standard deviation of five individual mice is shown.
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