IL-33 Signaling Regulates Innate and Adaptive Immunity to Cryptococcus neoformans

Abstract

Susceptibility to progressive infection with the fungus Cryptococcus neoformans is associated with an allergic pattern of lung inflammation, yet the factors that govern this host response are not clearly understood. Using a clinically relevant mouse model of inhalational infection with virulent C. neoformans H99, we demonstrate a role for IL-33–dependent signaling in host immune defense. Infection of BALB/c mice with 104 CFU of C. neoformans H99 caused a time-dependent induction of IL-33 with accumulation of type 2 pulmonary innate lymphoid cells and alternatively activated macrophages in the lungs as well as Th2-polarized CD4+ T cells in draining lymph nodes. IL-33R subunit T1/ST2-deficient (T1/ST2−/−) mice infected with C. neoformans H99 had improved survival with a decreased fungal burden in the lungs, spleen, and brain, compared with wild-type mice. Signaling through T1/ST2 was required for the accumulation and early production of IL-5 and IL-13 by lung type 2 pulmonary innate lymphoid cells. Further analysis of T1/ST2−/− mice revealed increased fungicidal exudate macrophages in the lungs and decreased C. neoformans–specific Th2 cells in the mediastinal lymph nodes. T1/ST2 deficiency also diminished goblet cell hyperplasia, mucus hypersecretion, bronchoalveolar lavage eosinophilia, alternative activation of macrophages, and serum IgE. These observations demonstrate that IL-33–dependent signaling contributes to the expansion of innate type 2 immunity and subsequent Th2-biased lung immunopathology that facilitates C. neoformans growth and dissemination.

Crucial and Diverse Role of the Interleukin-33/ST2 Axis in Infectious Diseases

“…In another study, ST2-deficient mice had improved survival and lower C. neoformans burdens in the lungs, spleen, and brain (61). The ST2 deficiency led to a decrease in production of IL-5 and IL-13 by innate type 2 lymphoid cells and impaired Th2 mucosal immunity (61).…”

Cryptococcus: from environmental saprophyte to global pathogen

“…Collectively, these mechanisms generate an environment that is dominated by anti-inflammatory markers such as IL-4 and IL-33 (REFS 39–41), which, as a consequence, reduce cryptococcal killing by the immune system 38, 42 . Therefore, modulating natural immune responses to cryptococcal infection towards a more pro-inflammatory profile offers one potential avenue for treatment.…”

The role of IL-33/ST2L signals in the immune cells

“…Although characteristics of ILCs that respond to IL-33 are still being delineated, recent studies have indicated that IL-33 induces production of large amounts of IL-5 and IL-13 by group 2 innate lymphoid cells (ILC2s) in several diseases models [50,[56][57][58] (Fig. 2).…”