How Cd1d protects mice during natural infection

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Summary Natural killer T cells (NKT) are a special class of lymphocytes that recognize lipid antigens presented by CD1 family molecules. They are strongly conserved throughout mammalian evolution. Nonetheless, we do not understand what essential function(s) lipid specific T cells serve to promote the health of the species. To determine if there is a common mouse microorganism that NKT cells play a role in protection from, we co- housed CD1d deficient mice with pet store mice, which bear a relatively high natural microbial burden, to permit physiological transmission of microbes. Adult CD1d deficient mice were generally healthy when co- housed. However, CD1d deficient pups did not survive to term in Cd1d+/- x Cd1d+/- breeding cages where there was normal microbial exposure (i.e. only WT or CD1d heterozygous pups survived). This suggests the hypothesis that NKT cells play a critical role in protecting the developing fetus in the face of diverse microbial infection and may explain their conservation throughout mammalian evolution. This is an exciting new finding and important hypothesis to test. However, key information is required before mechanistic R01 type research can be proposed. In this R21 proposal, we seek to understand whether maternal NKT cells are activated by fetal (trophoblast) CD1d and required for protection of the fetus, and if fetal demise is associated with excess inflammation and/or a specific microbial infection.