FCRL5 Delineates Functionally Impaired Memory B Cells Associated with Plasmodium falciparum Exposure

Abstract

Exposure to Plasmodium falciparum is associated with circulating “atypical” memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals. Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda. Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs. Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs. Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation. Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs. Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum.

Fc Receptor–like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue–like Memory B Cells

“…+ cells described in HCV-MC patients (7,39 2 TLM B cells (36,40), in agreement with our study. Importantly, FCRL5 expression was found associated with markedly compromised BCR signaling and Ab production and it was suggested that FCRL5 marks dysfunctional cells (36,40).…”

“…Importantly, FCRL5 expression was found associated with markedly compromised BCR signaling and Ab production and it was suggested that FCRL5 marks dysfunctional cells (36,40). Most of the genes that we identified differentially expressed between the two subsets of TLM B cells were also detected in the malaria studies, which compared TLM B cells to classical memory B cells.…”

“…RTN4R was the most differentially expressed gene between the two TLM B cell subsets. Notably, RTN4R was also found in a recent microarray study to be the most differentially expressed gene between TLM B cells and classical memory B cells obtained from children exposed to malaria (36). RTN4R protein plays critical roles in the CNS and has multiple binding partners, including BAFF (37), and was shown to be expressed by activated human B cells (38).…”

T-bet+ B cells are induced by human viral infections and dominate the HIV gp140 response

“…We also observed involvement of T-bet + B cells in the response to HIV infection, as T-bet was rapidly induced in B cells during the acute phase and T-bet We and others have previously demonstrated an expansion of CD21 -B cell subsets induced by Th1-type human infections, including HIV, malaria, and hepatitis C (30,31,34,35,(60)(61)(62)(63), and expansion of a clonal CD21 -subset has been described during hepatitis B-and hepatitis C-associated mixed cryoglobulinemia (64)(65)(66). Interestingly, maintenance of expanded CD21 -cells in each of these infections appears to be dependent upon pathogen load (34,35,60,(67)(68)(69).…”

“…Similarly, chronic lymphochoriomeningitis (LCMV) viremia is controlled to low levels only in the presence of T-bet + B cells via a chiefly IgG2a-dependent mechanism (6). We previously identified a subset of T-bet-expressing B cells in healthy human blood (26), and B cells expressing either TBX21 transcript or T-bet protein have been described in the context of autoimmune disease, chronic hepatitis C infection, and malaria infection (27)(28)(29)(30)(31), but the biological niche of this population in humans has not been defined.…”