Down-regulation of MINCLE expression on macrophages by IL-4 as a possible mechanism of thwarted Th17 vaccination responses by helminth infection
SCHICK J. 1, ALTUNAY M. 1, LACORCIA M. 2,3, VÖHRINGER D. 4, PRAZERES DA COSTA C. 2,3, LANG R. 1
1 Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany; 2 Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Center for Global Health, Technische Universität München, München, Germany; 3 Center for Global Health, Technical University Munich, München, Germany; 4 Infektionsbiologische Abteilung, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
Macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor that senses trehalose-6,6-dimycolate (TDM), a major component of the mycobacterial cell wall. This recognition activates antigen-presenting cells that direct protective immune responses toward the production of Th1/Th17 cytokines. In contrast, helminth infection results in high production of the Th2 cytokines such as IL-4, IL-5, and IL-13, which downregulates Mincle expression in murine and human macrophages in vitro. We hypothesized that the IL-4-biased immune status in helminth infection could interfere with Th1/Th17 immune responses in response to mycobacterial infection or vaccination with Mincle-dependent adjuvants. In this study, we elucidate the effect of IL-4 on Mycobacterium bovis Bacille Calmette-Guerin (BCG)-infected macrophages and determine the functional impact of helminth infection on Mincle-dependent immune responses. We found that IL-4 downregulates Mincle expression in BCG-infected macrophages, and in vivo studies revealed decreased expression of Mincle on myeloid cells in IL-4 plasmid injected mice. Moreover, mice infected with the helminth Nippostrongylus brasiliensis and vaccinated with a Mincle-dependent adjuvant exhibited a disrupted IL-17 response. Increased production of IL-4 in the spleens of helminth-infected was associated with a disrupted IL-17 response to vaccination. To tested a causal role of Th2 cytokines by using Il4/Il13 deficient mice, and indeed found restored production of IL-17 in helminth-infected mice. We conclude that helminth infection reduces IL-17 production to Mincle-dependent immunization in organ and adjuvant specific manner via the production of IL-4/IL-13. Our findings reveal a possible mechanism whereby IL-4 interferes with the production of IL-17 via a Mincle-dependent pathway.