Intestinal γδ T-cell receptor-bearing intraepithelial lymphocytes (γδ IELs) play a multifaceted role in maintaining mucosal homeostasis. In order to investigate the relationship between O-glycosylation and inflammation, we carried out an in-depth mass spectrometric comparison of the intestinal O-glycosylation profile of mice lacking γδ IELs (TCRδ −/− ) and of their wild-type (WT) littermates. A total of 69 nonsulfated and 59 sulfated compositional types of O-glycans were identified in the small

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... intestine and colon of TCRδ −/− and WT mice. Our results demonstrated structural differences in intestinal glycosylation in TCRδ −/− mice compared with WT littermates. TCRδ −/− colons contained a lower proportion of core-2 structures and an increased proportion of core-1 structures whereas TCRδ −/− small intestines had a decreased percentage of core-3 structures. The glycan antennae in TCRδ −/− colon and small intestine showed altered structural diversity compared with WT mice. There were significant differences in the sialylated species between the TCRδ −/− and WT mice with the sialylated Tn antigen found exclusively in the TCRδ −/− small intestine, whereas the sulfation pattern remained mostly unchanged. These findings provide novel molecular insights underpinning the role of γδ IELs in maintaining gut homeostasis.