In vitro induction of an atypical memory B cell phenotype in human B cells

Abstract

Abstract Several chronic human infectious diseases including malaria are associated with a large expansion of an unusual population of memory B cells(MBCs) which is referred to as atypical MBCs in malaria. Atypical MBCs in malaria are CD21−, CD27−, CD11c+, FcRL5+, high expression of the transcription factor, T-bet, and have accumulated somatic hyper mutations. These atypical MBCs showed poor B cell receptors signaling and B cell function, ex vivo. These studies suggest that atypical MBCs may contribute to the slow, inefficient acquisition of immunity to malaria in African children. However, the mechanisms by which atypical MBCs are induced during chronic infectious diseases are not known. Recently acute febrile malaria was correlated in African children with increases in peripheral blood TH1-type T follicular helper T cells that secrete inflammatory cytokines, including IFN-γ, and are impaired in their helper function. These results suggested that such T cells or their products may contribute to generation of atypical MBCs. We investigated the conditions under which human B cells can induce an atypical MBC phenotype in vitro. Studying tonsillar B cells we showed that triple combined signaling pathway, BCR, TLR and IFNγ is required for the induction of the malaria-associated atypical MBCs in vitro. In addition, human peripheral blood B cells were induced to express T-bet when incubated anti-Ig and the supernatants of peripheral blood mononuclear cells stimulated by parasite-infected red blood cells. Taken together these results suggest that atypical MBCs may be the product of B cell antigen engagement in the highly inflammatory environments that develop during chronic infections.