Migration-induced cell shattering due to DOCK8 deficiency causes a type 2-biased helper T cell response

Nat Immunol. 2020 Dec;21(12):1528-1539. doi: 10.1038/s41590-020-0795-1. | PubMed

Caitlin Schneider^1,2, Connie Shen^1,2, Angelica A Gopal^2,3,4, Todd Douglas^1,2, Benjamin Forestell^1,2, Keith D Kauffman⁵, Dakota Rogers^2,3, Patricio Artusa^2,3, Qian Zhang^6,7, Huie Jing⁶, Alexandra F Freeman⁶, Daniel L Barber⁵, Irah L King⁸, Maya Saleh^9,10, Paul W Wiseman¹¹, Helen C Su⁶, Judith N Mandl^12,13,14

1. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
2. McGill Research Centre for Complex Traits, McGill University, Montreal, Quebec, Canada.
3. Department of Physiology, McGill University, Montreal, Quebec, Canada.
4. Massachusetts General Hospital, Boston, MA, USA.
5. T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
6. Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
7. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, NY, USA.
8. Meakins-Christie Laboratories, Department of Microbiology and Immunology, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
9. Department of Medicine, McGill University, Montreal, Quebec, Canada.
10. University of Bordeaux, Bordeaux, France.
11. Department of Chemistry and Department of Physics, McGill University, Montreal, Quebec, Canada.
12. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada. judith.mandl@mcgill.ca.
13. McGill Research Centre for Complex Traits, McGill University, Montreal, Quebec, Canada. judith.mandl@mcgill.ca.
14. Department of Physiology, McGill University, Montreal, Quebec, Canada. judith.mandl@mcgill.ca.

Abstract

Mutations that impact immune cell migration and result in immune deficiency illustrate the importance of cell movement in host defense. In humans, loss-of-function mutations in DOCK8, a guanine exchange factor involved in hematopoietic cell migration, lead to immunodeficiency and, paradoxically, allergic disease. Here, we demonstrate that, like humans, Dock8-/- mice have a profound type 2 CD4+ helper T (TH2) cell bias upon pulmonary infection with Cryptococcus neoformans and other non-TH2 stimuli. We found that recruited Dock8-/-CX3CR1+ mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1β that drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by CD4+ T cells. Blocking IL-1β, GM-CSF or caspase activation eliminated the type-2 skew in mice lacking Dock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and TH2 cell differentiation. This reveals an important role for cell death in driving type 2 signals during infection, which may have implications for understanding the etiology of type 2 CD4+ T cell responses in allergic disease.

Presented By Caitlin Schneider | ORCID iD