The IL-33 receptor (ST2) regulates early IL-13 production in fungus-induced allergic airway inflammation.

Allergic airway inflammation (AAI) in response to environmental antigens is an increasing medical problem, especially in the Western world. Type 2 interleukins (IL) are central in the pathological response but their importance and cellular source(s) often rely on the particular allergen. Here, we highlight the cellular sources and regulation of the prototypic type 2 cytokine, IL-13, during the establishment of AAI in a fungal infection model using Cryptococcus neoformans. IL-13 reporter mice revealed a rapid onset of IL-13 competence within innate lymphoid cells type 2 (ILC2) and IL-33R(+) T helper (Th) cells. ILC2 showed IL-33-dependent proliferation upon infection and significant IL-13 production. Th cells essentially required IL-33 to become either GATA3(+) or GATA3(+)/Foxp3(+) hybrids. GATA3(+) Th cells almost exclusively contributed to IL-13 production but hybrid GATA3(+)/Foxp3(+) Th cells did not. In addition, alveolar macrophages upregulated the IL-33R and subsequently acquired a phenotype of alternative activation (Ym1(+), FIZZ1(+), and arginase-1(+)) linked to type 2 immunity. Absence of adaptive immunity in rag2(-/-) mice resulted in attenuated AAI, revealing the need for Th2 cells for full AAI development. Taken together, in pulmonary cryptococcosis ILC2 and GATA3(+) Th2 cells produce early IL-13 largely IL-33R-dependent, thereby promoting goblet cell metaplasia, pulmonary eosinophilia, and alternative activation of alveolar macrophages.

T1/ST2 promotes T helper 2 cell activation and polyfunctionality in bronchopulmonary mycosis.

Interleukin (IL)-33 enhances T helper (Th)2 immunity via its receptor T1/ST2. Infection with the yeast-like pathogen Cryptococcus neoformans is usually controlled by a Th1-mediated immune response. The mechanisms responsible for nonprotective Th2 immunity leading to allergic inflammation in pulmonary cryptococcosis are still not fully understood. Using a murine pulmonary model of C. neoformans infection, we report that T1/ST2 expression correlates with the intensity of Th2 activation, as demonstrated by the expression of CD25 and CD44 and downregulation of CD62L. Antigen-specific T1/ST2(+) Th cells are the primary source of the Th2 cytokines IL-5 and IL-13 as compared with wild-type T1/ST2(-) Th cells or Th cells from T1/ST2(-/-) mice. In addition, T1/ST2(+) Th cells almost exclusively contain bi- and trifunctional Th2 cytokine-producing Th cells compared with T1/ST2(-) Th cells or Th cells from T1/ST2(-/-) mice. Finally, T1/ST2-driven Th2 development resulted in defective pulmonary fungal control. These data demonstrate that T1/ST2 directs Th2 cell activation and polyfunctionality in allergic bronchopulmonary mycosis.

Lack of IL-4 receptor expression on T helper cells reduces T helper 2 cell polyfunctionality and confers resistance in allergic bronchopulmonary mycosis.

T helper (Th)1 and Th2 cells play decisive roles in the regulation of resistance vs. susceptibility to pulmonary cryptococcosis. To study the function of interleukin (IL)-4 receptor (IL-4R) on Th cells in pulmonary cryptococcosis, we infected mice specifically lacking IL-4Rα on CD4(+) T cells (Lck(Cre)IL-4Rα(-/lox) mice) and IL-4Rα(-/lox) controls. Lck(Cre)IL-4Rα(-/lox) mice developed enhanced resistance accompanied by reduced pulmonary allergic inflammation and diminished production of the Th2 cytokines IL-4, IL-5, and IL-13 as compared with IL-4Rα(-/lox) mice. Polyfunctional antigen-specific Th2 cells producing simultaneously two or three Th2 cytokines were reduced in infected Lck(Cre)IL-4Rα(-/lox) mice, pointing to a critical role of polyfunctional Th2 cells for disease progression. Reduced Th2 polyfunctionality was associated with fewer pulmonary alternatively activated macrophages. This work is the first direct evidence for a critical contribution of the IL-4R on Th cells to Th2-dependent susceptibility during allergic bronchopulmonary mycosis. Moreover, the data demonstrate that the quality of the Th2 response has an impact on type 2 inflammation. The analysis of polyfunctional Th2 cells may be useful for monitoring the course of the disease.

NAD degradation and regulation of CD38 expression by human monocytes/macrophages.

In recent years, evidence has accumulated that NAD+ serves as a precursor of metabolites that are involved in a number of regulatory processes. In this work we show that extracellularly added NAD+ was rapidly degraded by intact human monocytes to nicotinamide and ADP-ribose. Besides these main products, minor amounts of AMP, ADP and cADP-ribose were formed. Expression of CD38, which has been identified as NAD+-glycohydrolase (EC 3.2.2.6) degrading NAD+ into nicotinamide and ADP-ribose, was determined on freshly isolated human monocytes by flow cytometry and RT-PCR. Upon ligation with anti-CD38 mAb, CD38 underwent internalization, shedding and new expression. As monocytes possess an intracellular CD38 pool, it could serve as a source for newly expressed CD38. Differentiation of monocytes to macrophages resulted in down-regulation of surface expression of CD38. This decrease correlates with a reduction in NADase activity, indicating that the amount of functional active CD38 molecules decrease during differentiation. As CD38 mRNA was found to be diminished in macrophages, regulation of the gene product seems to occur at the level of transcription or mRNA stability.