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.

Author Summary

Humans often inhale potentially pathogenic fungi in the environment. While CD4+ helper T (Th) cells are required for protection against invasive disease, a subset of Th cells, called Th2 cells, are associated with increased mortality and allergy/asthma morbidity. Our study aimed to unravel the cellular and molecular basis of pulmonary Th2 cell induction in response to lethal infection with Cryptococcus neoformans. Antigen-presenting cells coordinate naïve Th cell priming and differentiation, but the precise leukocyte responsible for Th2 cell expansion to pulmonary cryptococcal infection has not been determined. Using an experimental mouse model of pulmonary cryptococcosis, we show that a subset of lung-resident dendritic cells is uniquely required for Th2 cell induction. We additionally sought to identify the molecular signal received by the host that allows dendritic cells to selectively induce Th2 cells. Since parasites and fungi elicit Th2 cell responses and both produce chitin, a molecule not found in vertebrates, we hypothesized that recognition of fungal chitin is a determinant of fungal disease. Here, we demonstrate that C. neoformans chitin and the host-derived chitinase, chitotriosidase, promote Th2 cell accumulation and disease. These findings highlight a promising target of next generation therapies aimed at limiting immunopathology caused by pulmonary fungal infection.