Allergen Exposure in Lymphopenic Fas-Deficient Mice Results in Persistent Eosinophilia Due to Defects in Resolution of Inflammation

Front Immunol. 2018 Oct 30:9:2395. doi: 10.3389/fimmu.2018.02395. eCollection 2018.

Abstract

Asthma is characterized by chronic airway type-2 inflammation and eosinophilia, yet the mechanisms involved in chronic, non-resolving inflammation remain poorly defined. Previously, our group has found that when Rag-deficient mice were reconstituted with Fas-deficient B6 LPR T cells and sensitized and challenged, the mice developed a prolonged type-2-mediated airway inflammation that continued for more than 6 weeks after the last antigen exposure. Surprisingly, no defect in resolution was found when intact B6 LPR mice or T cell specific Fas-conditional knockout mice were sensitized and challenged. We hypothesize that the homeostatic proliferation induced by adoptive transfer of T cells into Rag-deficient mice may be an important mechanism involved in the lack of resolution. To investigate the role of homeostatic proliferation, we induced lymphopenia in the T cell-specific Fas-conditional knockout mice by non-lethal irradiation and sensitized them when T cells began to repopulate. Interestingly, we found that defective Fas signaling on T cells plus antigen exposure during homeostatic proliferation was sufficient to induce prolonged eosinophilic airway inflammation. In conclusion, our data show that the combination of transient lymphopenia, abnormal Fas-signaling, and antigen exposure leads to the development of a prolonged airway eosinophilic inflammatory phase in our mouse model of experimental asthma.

Keywords: Th1/Th2 cells; apoptosis; asthma; eosinophils; inflammation; lung; lymphopenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Allergens / immunology*
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • Disease Models, Animal
  • Disease Susceptibility
  • Eosinophilia / etiology*
  • Eosinophilia / metabolism*
  • Eosinophilia / pathology
  • Inflammation / etiology*
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Lymphopenia / etiology*
  • Lymphopenia / metabolism*
  • Lymphopenia / pathology
  • Mice
  • Mice, Knockout
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th2 Cells / immunology
  • Th2 Cells / metabolism
  • fas Receptor / deficiency*

Substances

  • Allergens
  • fas Receptor