CD200 Receptor Controls Sex-Specific TLR7 Responses to Viral Infection

Abstract

Immunological checkpoints, such as the inhibitory CD200 receptor (CD200R), play a dual role in balancing the immune system during microbial infection. On the one hand these inhibitory signals prevent excessive immune mediated pathology but on the other hand they may impair clearance of the pathogen. We studied the influence of the inhibitory CD200-CD200R axis on clearance and pathology in two different virus infection models. We find that lack of CD200R signaling strongly enhances type I interferon (IFN) production and viral clearance and improves the outcome of mouse hepatitis corona virus (MHV) infection, particularly in female mice. MHV clearance is known to be dependent on Toll like receptor 7 (TLR7)-mediated type I IFN production and sex differences in TLR7 responses previously have been reported for humans. We therefore hypothesize that CD200R ligation suppresses TLR7 responses and that release of this inhibition enlarges sex differences in TLR7 signaling. This hypothesis is supported by our findings that in vivo administration of synthetic TLR7 ligand leads to enhanced type I IFN production, particularly in female Cd200 ^−/− mice and that CD200R ligation inhibits TLR7 signaling in vitro. In influenza A virus infection we show that viral clearance is determined by sex but not by CD200R signaling. However, absence of CD200R in influenza A virus infection results in enhanced lung neutrophil influx and pathology in females. Thus, CD200-CD200R and sex are host factors that together determine the outcome of viral infection. Our data predict a sex bias in both beneficial and pathological immune responses to virus infection upon therapeutic targeting of CD200-CD200R.

Author Summary

Immune responses need to be carefully orchestrated to prevent disease due to an overactive immune system. Immunological checkpoints are provided by immune inhibitory receptors, which set a threshold for activation and dampen the immune system. In the case of a viral infection, this prevents pathology induced by the immune system, but on the other hand may prevent adequate removal of the virus. In this paper, we show that removal of such an immunological checkpoint in mice leads to rapid removal of corona virus, but also to more immune-induced disease symptoms in case of influenza virus infection. We observe this predominantly in female mice. We demonstrate that this particular checkpoint inhibits anti-viral responses that are naturally stronger in females. Release of this checkpoint enlarges these sex differences. Our findings have major implications for therapeutic use of blockers of this pathway, which are currently in clinical trials for the treatment of cancer, as we predict that female patients will have a stronger response to such therapeutics.