Fishing for a complement signal in the germinal center

The germinal center (GC) produces high-affinity antibody responses by subjecting B cells to iterative cycles of mutation and selection. GC B cells compete for survival signals like access to antigen for B cell receptor (BCR) stimulation and CD40 activation by T cells. Such signals favor selection of high-affinity B cells, but they are not the only signals involved in this process. Recently, Cumpelik et al. have identified B cell–intrinsic complement signaling as a modulator of GC dynamics.

The authors observed that human and mouse GC B cells down-regulate decay accelerating factor (DAF/CD55); DAF promotes C3 convertase decay on cell surfaces, reducing C3 activation. Notably, the GC B cell transcription factor BCL6 directly represses DAF transcription. Simultaneously, GC B cells up-regulate CD59, which blocks the membrane attack complex, suggesting a role for complement signaling, but not killing, in the GC.

To determine the effect of complement signaling on GC B cells, the authors created mouse strains lacking signaling to the complement components, C3a and C5a, on GC B cells. After immunization with model antigens, mutant mice had attenuated GC responses with impaired antibody magnitude and affinity. Overexpression of DAF on GC B cells phenocopied this response, suggesting that DAF down-regulation by GC B cells enables complement signaling crucial for effective GC responses. Using other complement pathway-deficient mice, including complement receptor 2 (CR2/CD21) knockout mice, they argue that the classical arm of complement activation, functioning through C3aR and C5aR, is responsible for this GC B cell phenotype.

How does complement signaling fit into the network of signals regulating the GC? The authors discovered that GC B cells lacking C3a and C5a receptors were unable to respond to BCR and CD40 stimulation through up-regulation of the downstream signaling factor, mTOR. These data indicate that complement signaling augments signals that drive B cell selection and, ultimately, high affinity antibody production. Further work is needed to understand whether complement signaling is necessary for GC responses to various types of immunogens and various antibody isotypes. Moreover, these findings raise important questions about how therapies targeting the complement cascade might alter humoral immunity.

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