title: Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection.
abstract: Pulmonary mycoses are often associated with type-2 helper T (Th2) cell responses. However, mechanisms of Th2 cell accumulation are multifactorial and incompletely known. To investigate Th2 cell responses to pulmonary fungal infection, we developed a peptide-MHCII tetramer to track antigen-specific CD4+ T cells produced in response to infection with the fungal pathogen Cryptococcus neoformans. We noted massive accruement of pathologic cryptococcal antigen-specific Th2 cells in the lungs following infection that was coordinated by lung-resident CD11b+ IRF4-dependent conventional dendritic cells. Other researchers have demonstrated that this dendritic cell subset is also capable of priming protective Th17 cell responses to another pulmonary fungal infection, Aspergillus fumigatus. Thus, higher order detection of specific features of fungal infection by these dendritic cells must direct Th2 cell lineage commitment. Since chitin-containing parasites commonly elicit Th2 responses, we hypothesized that recognition of fungal chitin is an important determinant of Th2 cell-mediated mycosis. Using C. neoformans mutants or purified chitin, we found that chitin abundance impacted Th2 cell accumulation and disease. Importantly, we determined Th2 cell induction depended on cleavage of chitin via the mammalian chitinase, chitotriosidase, an enzyme that was also prevalent in humans experiencing overt cryptococcosis. The data presented herein offers a new perspective on fungal disease susceptibility, whereby chitin recognition via chitotriosidase leads to the initiation of harmful Th2 cell differentiation by CD11b+ conventional dendritic cells in response to pulmonary fungal infection.
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Darin L
authors.initials: DL
authors.lastname: Wiesner
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Specht
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Chrono K
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Smith
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Liliane
authors.initials: L
authors.lastname: Mukaremera
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota.
authors.forename: S Thera
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Chun G
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Warren Alpert Medical School, Division of Biology and Medicine, Brown University, Providence, Rhode Island.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Nielsen
authors.affiliation: Division of Infectious Diseases and International Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota.
authors.forename: David R
authors.initials: DR
authors.lastname: Boulware
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota; Division of Infectious Diseases and International Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Bohjanen
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Jenkins
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Levitz
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D002686:Chitin / Q000276:immunology*; D003453:Cryptococcosis / Q000276:immunology*; D003455:Cryptococcus neoformans; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006596:Hexosaminidases / Q000276:immunology*; D008172:Lung Diseases, Fungal / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000946:Antigens, Fungal; D002686:Chitin; D006596:Hexosaminidases; C086400:chitotriosidase