Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin

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• 作者：Matthew T. Stier ; BS^a ; Melissa H. Bloodworth ; BS^a ; Shinji Toki ; PhD^b ; Dawn C. Newcomb ; PhD^a ; ^b ; Kasia Goleniewska ; MS^b ; Kelli L. Boyd ; DVM ; PhD^a ; Marc Quitalig^b ; Anne L. Hotard ; PhD^c ; Martin L. Moore ; PhD^c ; Tina V. Hartert ; MD ; MPH^b ; Baohua Zhou ; PhD^d ; Andrew N. McKenzie ; PhD^e ; R. Stokes Peebles Jr. ; MD^a ; ^b ; ^{stokes.peebles@vanderbilt.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Group 2 innate lymphoid cells ; IL-13 ; IL-33 ; thymic stromal lymphopoietin ; respiratory syncytial virus ; type 2 immunity (TH2)
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：138
• 期：3
• 页码：814-824.e11
• 全文大小：4398 K

文摘

Respiratory syncytial virus (RSV) is a major health care burden with a particularly high worldwide morbidity and mortality rate among infants. Data suggest that severe RSV-associated illness is in part caused by immunopathology associated with a robust type 2 response.

Objective

We sought to determine the capacity of RSV infection to stimulate group 2 innate lymphoid cells (ILC2s) and the associated mechanism in a murine model.

Methods

Wild-type (WT) BALB/c, thymic stromal lymphopoietin receptor (TSLPR) knockout (KO), or WT mice receiving an anti-TSLP neutralizing antibody were infected with the RSV strain 01/2-20. During the first 4 to 6 days of infection, lungs were collected for evaluation of viral load, protein concentration, airway mucus, airway reactivity, or ILC2 numbers. Results were confirmed with 2 additional RSV clinical isolates, 12/11-19 and 12/12-6, with known human pathogenic potential.

Results

RSV induced a 3-fold increase in the number of IL-13–producing ILC2s at day 4 after infection, with a concurrent increase in total lung IL-13 levels. Both thymic stromal lymphopoietin (TSLP) and IL-33 levels were increased 12 hours after infection. TSLPR KO mice did not mount an IL-13–producing ILC2 response to RSV infection. Additionally, neutralization of TSLP significantly attenuated the RSV-induced IL-13–producing ILC2 response. TSLPR KO mice displayed reduced lung IL-13 protein levels, decreased airway mucus and reactivity, attenuated weight loss, and similar viral loads as WT mice. Both 12/11-19 and 12/12-6 similarly induced IL-13–producing ILC2s through a TSLP-dependent mechanism.

Conclusion

These data demonstrate that multiple pathogenic strains of RSV induce IL-13–producing ILC2 proliferation and activation through a TSLP-dependent mechanism in a murine model and suggest the potential therapeutic targeting of TSLP during severe RSV infection.