C-type Lectin MCL Is an FcRγ-Coupled Receptor that Mediates the Adjuvanticity of Mycobacterial Cord Factor

Cord factor, also called trehalose-6,6'-dimycolate (TDM), is a potent mycobacterial adjuvant. We herein report that the C-type lectin MCL (also called Clec4d) is a TDM receptor that is likely to arise from gene duplication of Mincle (also called Clec4e). Mincle isknown to be an inducible receptor recognizing TDM, whereas MCL was constitutively expressed in myeloid cells. To examine the contribution of MCL in response to TDM adjuvant, we generated MCL-deficient mice. TDM promoted innate immune responses, such as granuloma formation, which was severely impaired in MCL-deficient mice. TDM-induced acquired immune responses, such as experimental autoimmune encephalomyelitis (EAE), was almost completely dependent on MCL, but not Mincle. Furthermore, by generating Clec4e^gfp reporter mice, we found that MCL was also crucial for driving Mincle induction upon TDM stimulation. These results suggest that MCL is an FcRγ-coupled activating receptor that mediates the adjuvanticity ofTDM. •MCL is an ITAM-coupled TDM receptor that arises from gene duplication of Mincle•Innate and acquired immunity induced by TDM are impaired in MCL-deficient mice•MCL drives Mincle expression in dendritic cells upon TDM stimulation•MCL, but not Mincle, is critically involved in EAE induced by TDM adjuvant.