Description: IL-4 is critical for optimal B cell activation and germinal center B cell expansion in T-dependent immune responses; however, the underlying mechanism remains elusive. In the current study, we found that primary B cells express little Igα and Igβ protein despite substantial levels of mRNA. IL-4 markedly upregulates Igα and Igβ protein expression that requires STAT6. Elevated Igα and Igβ protein form heterodimers that associate with IgM and significantly promote IgM maturation and surface IgM expression, resulting in amplified BCR-initiated signaling that is Lyn dependent. In vivo, we found that pregerminal center B cells express upregulated Igα, Igβ, and surface IgM expression, in conjunction with elevated BCR-triggered phosphorylated ERK ex vivo, that are dependent on IL-4 and reversed by in vivo administration of neutralizing anti–IL-4 Ab. Thus, this study elucidates a novel mechanism for cross-talk between the IL-4 and BCRs that programs enhancement of subsequent BCR signaling.

Description: The protective immunity induced by the whole-killed parasite vaccine against malarial blood-stage infection is dependent on the CD4 + T cell response. However, the mechanism underlying this robust CD4 + T cell response elicited by the whole-killed parasite vaccine is still largely unknown. In this study, we observe that immunization with Plasmodium yoelii –parasitized RBC lysate activates complement C5 and generates C5a. However, the protective efficacy against P. yoelii 17XL challenge is considerably reduced, and the malaria-specific CD4 + T cell activation and memory T cell differentiation are largely suppressed in the C5aR-deficient (C5aR –/– ) mice. An adoptive transfer assay demonstrates that the reduced protection of C5aR –/– mice is closely associated with the severely impaired CD4 + T cell response. This is further confirmed by the fact that administration of C5aR antagonist significantly reduces the protective efficacy of the immunized B cell–deficient mice. Further study indicates that the defective CD4 + T cell response in C5aR –/– mice is unlikely involved in the expansion of CD4 + CD25 + Foxp3 + T cells, but strongly linked to a defect in dendritic cell (DC) maturation and the ability to allostimulate CD4 + T cells. These results demonstrate that C5aR signaling is essential for the optimal induction of the malaria-specific CD4 + T cell response by the whole-killed parasite vaccine through modulation of DCs function, which provides us with new clues to design an effective blood-stage subunit vaccine and helps us to understand the mechanism by which the T cell response is regulated by the complement system.

Description: Ag-specific CD8 + T cell contraction (contraction), which occurs after the resolution of infection, is critical for homeostasis of the immune system. Although complement components regulate the primary CD8 + T cell response, there is insufficient evidence supporting their role in regulating contraction and memory. In this study, we show that C3-deficient ( C3 –/– ) mice exhibited significantly less CD8 + T cell contraction than did wild-type mice postinfection with recombinant Listeria monocytogenes expressing OVA. Kinetic analyses also revealed decreased contraction in mice treated with cobra venom factor to deplete C3, which was consistent with the results in C3 –/– recipient mice transplanted with bone marrow cells from the same donors as wild-type recipient mice. The phenotypes of memory cells generated by C3 –/– mice were not altered compared with those of wild-type mice. Further, C5aR signaling downstream of C3 was not involved in the regulation of contraction. Moreover, the regulation of contraction by C3 may be independent of the duration of antigenic stimulation or the functional avidity of effector CD8 + T cells. However, reduced contraction in C3 –/– mice was accompanied by a decrease in the proportion of KLRG-1 hi (killer-cell lectin-like receptor G1) CD127 lo short-lived effector cells at the peak of the response and correlated with a reduction in the levels of inflammatory cytokines, such as IL-12 and IFN-, produced early postinfection. These results provide new insights into the role of systemic C3 in regulating contraction following intracellular bacterial infection and may help to develop vaccines that are more effective.

Description: B1a cells, particularly the PD-L2 + B1a cell subset, are enriched with autoantigen-specific receptors. However, the underlying molecular mechanism responsible for the skewed selection of autoreactive B1a cells remains unclear. In this study, we find that B1 cells express only Ras guanyl nucleotide–releasing protein (RasGRP) 1, whereas B2 cells express mostly RasGRP3 and little RasGRP1. RasGRP1 is indispensable for transduction of weak signals. RasGRP1 deficiency markedly impairs B1a cell development and reduces serum natural IgM production; in particular, B1a cells that express autoantigen receptors, such as anti-phosphatidylcholine B1a cells, are virtually eliminated. Thus, unlike Btk and other signalosome components, RasGRP1 deficiency selectively affects only the B1a cell population with autoantigen receptors rather than the entire pool of B1a cells.