TACI contributes to plasmodium yoelii host resistance by controlling t follicular helper cell response and germinal center formation

Abstract

The delay in parasite-specific B cell development leaves people in malaria endemic areas vulnerable to repeated Plasmodium infections. Here, we investigated the role of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a molecule involved in the generation of antigen-specific antibody secreting cells, in host response to non-lethal Plasmodium yoelii infection. We found that TACI deficiency not only resulted in higher peak parasitemia levels in P. Yoelii challenged mice, but also led to a delay in parasite clearance and anti-P. Yoelii Merozoite Surface Protein 1(C-terminal 19-kDa fragment [rMSP-119]) protein and anti-rMSP-119 and anti-P. Yoelii IgG antibody development. There was also a delay in the generation of splenic high affinity antibody secreting cells that recognize rMSP-119 protein as compared to wild-type mice. Interestingly, coinciding with the delay in parasite clearance there was a delay in the resolution of T follicular helper (TFH) cell and germinal center (GC) B cell responses in TACI-/-mice. The persistence of TFH and GC B cells is likely a result of enhanced interaction between TFH and GC B cells because inducible costimulator ligand (ICOSL) expression was significantly higher on TACI-/-GC B cells than wild-type cells. The difference in the kinetics of GC reaction appeared to also impact the emergence of plasma cells (PC) because there was a delay in the generation of TACI-/-mice PC. Nevertheless, following the recovery from P. Yoelii infection, TACI-/-and wild-type mice were both protected from a rechallenge infection. Establishment of protective B cell response was responsible for the resolution of parasitemia because B cells purified from recovered TACI-/-or wild-type mice were equally protective when introduced to naïve wild-type mice prior to P. Yoelii challenge. Thus, despite the increased susceptibility of TACI-/-mice to P. Yoelii infection and a delay in the development of protective antibody levels, TACI-/-mice are able to clear the infection and resist rechallenge infection.