Invariant natural killer T cells (iNKT cells) rapidly produce cytokines in response to CD1d-presented lipid antigens. In Cell, An et al. report that the commensal gut bacterium Bacteroides fragilis limits iNKT cell numbers early in life and this results in protection against colitis in adults. B. fragilis expresses an enzyme, SPT, required for sphingolipid biosynthesis. Wild-type bacteria synthesize α-galactosylceramides that can be loaded onto CD1d molecules; however, these molecules fail to stimulate iNKT cells and function to competitively inhibit other lipid molecules for presentation by CD1d. B. fragilis colonization in neonatal mice limits iNKT cell proliferation and diminishes the total number of iNKT cells. However germ-free mice or those monocolonized by B. fragilis SPT mutants have more iNKT cells in the gut and thus develop heightened cytokine responses when challenged with agonist antigens of iNKT cells. Why iNKT cell numbers are particularly sensitive within an early developmental window remains unknown, but these findings suggest ways of intervening with iNKT cell responses.

Cell 156, 123–133 (2014)