Chitin Recognition via Chitotriosidase Promotes Pathologic Type-2 Helper T Cell Responses to Cryptococcal Infection

Darin L. Wiesner, Charles A. Specht, Chrono K. Lee, Kyle D. Smith, Liliane Mukaremera, S. Thera Lee, Chun G. Lee, Jack A. Elias, Judith N. Nielsen, David R. Boulware, Paul R. Bohjanen, Marc K. Jenkins, Stuart M. Levitz, Kirsten Nielsen

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

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.

Original languageEnglish (US)
Article numbere1004701
Pages (from-to)1-28
Number of pages28
JournalPLoS pathogens
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Wiesner et al.

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