Abstract
CD200 receptor 1(CD200R1) signalling limits myeloid cell responses and reduces autoimmunity, alloimmunity and viral‐mediated immunopathology, but has never been examined in the context of eosinophilic inflammation. Susceptibility to lung fungal infection is associated with T‐helper 2 (Th2) cytokine dominated responses and strong eosinophilic pathology. Blockade of CD200R1 enhances type I cytokine responses in many infectious and non‐infectious settings and so may promote a more protective response to fungal infection. By contrast, we demonstrate that, rather than promoting type I cytokine responses, CD200R1 blockade enhanced eosinophilia in a mouse model of Cryptococcus neoformans infection, whereas CD200R1 agonism reduced lung eosinophilia – with neither strategy completely altering fungal burden. Thus, we reveal a surprising disconnect between pulmonary eosinophilia and cryptococcal burden and dissemination. This research has 2 important implications. Firstly, a lack of CD200R1 signalling enhances immune responses regardless of cytokine polarisation, and secondly reducing eosinophils does not allow protective immunity to develop in susceptible fungal system. Therefore, agonists of CD200R1 may be beneficial for eosinophilic pathologies.
Highlights
The pleiotropic functions of myeloid cells require tight regulation to promote immunity to potentially harmful pathogens whilst limiting immunopathology
The C. neoformans susceptible C57BL/6 mouse model was utilized to dissect the role of CD200R1 in modulating T-helper 2 (Th2) inflammation and fungal clearance
As previously reported [8], a high level of CD200R1 expression was detected on alveolar CD11c+ macrophages in the airways and lungs of naıve mice, with expression remaining high upon C. neoformans infection (Fig. 1C and 1D)
Summary
The pleiotropic functions of myeloid cells require tight regulation to promote immunity to potentially harmful pathogens whilst limiting immunopathology. This regulation is achieved by both soluble factors and cell contact-dependent interactions, for example those mediated through CD200 receptor (CD200R1). CD200R1 is type 1 transmembrane protein and member of the immunoglobulin superfamily that is predominantly expressed by cells of the myeloid lineage. Ligation with the more broadly distributed ligand, CD200, delivers a unidirectional inhibitory signal to the myeloid cell [1]. Mice lacking CD200 display elevated numbers of activated macrophages and develop more aggressive autoimmune diseases [2, 3], suggesting that CD200 restrains the tonic activation of macrophages to promote homeostasis. Immunotherapeutic administration of CD200 alleviates excessive inflammation seen in auto- and alloimmune conditions [4,5,6]
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