Scientific Publications by FDA Staff

Proc Natl Acad Sci U S A 2015 Jul 28;112(30):E4094-103

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection.

Allman WR, Dey R, Liu L, Siddiqui S, Coleman AS, Bhattacharya P, Yano M, Uslu K, Takeda K, Nakhasi HL, Akkoyunlu M

The TNF family member, transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), is a key molecule for plasma cell maintenance and is required in infections where protection depends on antibody response. Here, we report that compared with WT mouse, TACI KO Muvarphis expressed lower levels of Toll-like receptors (TLRs), CD14, myeloid differentiation primary response protein 88, and adaptor protein Toll/IL-1 receptor domain-containing adapter-inducing IFN-beta and responded poorly to TLR agonists. Analysis of Muvarphi phenotype revealed that, in the absence of TACI, Muvarphis adapt the alternatively activated (M2) phenotype. Steady-state expression levels for M2 markers IL-4Ralpha, CD206, CCL22, IL-10, Arg1, IL1RN, and FIZZ1 were significantly higher in TACI KO Muvarphi than in WT cells. Confirming their M2 phenotype, TACI-KO Mvarphis were unable to control Leishmania major infection in vitro, and intradermal inoculation of Leishmania resulted in a more severe manifestation of disease than in the resistant C57BL/6 strain. Transfer of WT Muvarphis to TACI KO mice was sufficient to significantly reduce disease severity. TACI is likely to influence Mvarphi phenotype by mediating B cell-activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL) signals because both these ligands down-regulated M2 markers in WT but not in TACI-deficient Muvarphis. Moreover, treatment of Muvarphis with BAFF or APRIL enhanced the clearance of Leishmania from cells only when TACI is expressed. These findings may have implications for understanding the shortcomings of host response in newborns where TACI expression is reduced and in combined variable immunodeficiency patients where TACI signaling is ablated.