Inhibition of stearoyl-CoA desaturases suppresses follicular help T- and germinal center B- cell responses

Abstract

Stearoyl-CoA desaturases (SCD) are endoplasmic reticulum (ER)-associated enzymes that catalyze the synthesis of the monounsaturated fatty acids (MUFAs). As such, SCD play important roles in maintaining the intracellular balance between saturated fatty acid (SFAs) and MUFAs. The roles of SCD in CD4⁺ T-helper cell responses are currently unexplored. Here, we have found that murine and human follicular helper T (T_FH ) cells express higher levels of SCD compared to non-T_FH cells. Further, the expression of SCD in T_FH cells is dependent on the T_FH lineage-specification transcription factor BCL6. We found that the inhibition of SCD impaired T_FH cell maintenance and shifted the balance between T_FH and follicular regulatory T (T_FR ) cells in the spleen. Consequently, SCD inhibition dampened germinal center B-cell responses following influenza immunization. Mechanistically, we found that SCD inhibition led to increased ER stress and enhanced T_FH cell apoptosis in vitro and in vivo. These results reveal a possible link between fatty acid metabolism and cellular and humoral responses induced by immunization or potentially, autoimmunity.

Keywords: Endoplasmic reticulum stress; Follicular help T cells; Germinal center B cells; Lipid metabolism; Stearoyl-CoA desaturase 1.