c-Myb Regulates the T-Bet-Dependent Differentiation Program in B Cells to Coordinate Antibody Responses

Abstract

Humoral immune responses are tailored to the invading pathogen through regulation of key transcription factors and their networks. This is critical to establishing effective antibody-mediated responses, yet it is unknown how B cells integrate pathogen-induced signals to drive or suppress transcriptional programs specialized for each class of pathogen. Here, we detail the key role of the transcription factor c-Myb in regulating the T-bet-mediated anti-viral program. Deletion of c-Myb in mature B cells significantly increased serum IgG2c and CXCR3 expression by upregulating T-bet, normally suppressed during Th2-cell-mediated responses. Enhanced expression of T-bet resulted in aberrant plasma cell differentiation within the germinal center, mediated by CXCR3 expression. These findings identify a dual role for c-Myb in limiting inappropriate effector responses while coordinating plasma cell differentiation with germinal center egress. Identifying such intrinsic regulators of specialized antibody responses can assist in vaccine design and therapeutic intervention in B-cell-mediated immune disorders.

Induction of brain‐infiltrating T‐bet–expressing B cells in multiple sclerosis

“…24 These results are also consistent with our previous findings that CXCR3 + T cells, including Th17.1, are abundant within the CNS, 20,24 suggesting a common CXCR3-driven lymphocyte recruitment pathway in MS. 24,36,37 Other studies have also put forward CXCR5 and its ligand CXCL13 as important contributors to B-cell recruitment to the CNS. 13,14 This points to a central role of IFNγ-associated CXCR3 + B-cell subsets in the meningeal process. Hence, the CXCR5/CXCL13 axis is probably related to local organization rather than recruitment of pathogenic B (and T) cells, 39,40 in a process similar to that in secondary lymphoid organs.…”

“…12 In these cases, IFNγ induces the expression of the T-box transcription factor T-bet, resulting in enhanced Ig class switching and CXC chemokine receptor 3 (CXCR3) expression in murine B cells. 13,14 Interestingly, B-cell-intrinsic T-bet expression associates with increased pathogenic responses 14,15 and is induced by systemic infections, 16 a major environmental trigger in MS. 17 Toll-like receptor 9 (TLR9), which binds to pathogen-related CpG-DNA, integrates with the B-cell receptor (BCR), CD40, and cytokine signals to stimulate T-bet + B-cell development. 18,19 Additionally, B cells from MS patients were previously reported to exhibit an enhanced proinflammatory phenotype when activated with IFNγ and TLR9 ligand CpG-DNA.…”

Basics of memory B‐cell responses: lessons from and for the real world

“…The high levels of T‐bet expression in atypical memory B cells are associated with decreased BCR signaling and a switch from IgG1 to IgG3 surface expression . In some cases, T‐bet expression limits the ability of B cells to differentiate into germinal center B cells, and ultimately results in reduced IgG antibody titers, though in other cases it appears that T‐bet expression actually enhances serum IgG2c levels . Hence, severe malaria is associated with an inflammatory environment that results in a defective adaptive immune response.…”

“…88 In some cases, T-bet expression limits the ability of B cells to differentiate into germinal center B cells, and ultimately results in reduced IgG antibody titers, 89 though in other cases it appears that T-bet expression actually enhances serum IgG2c levels. 24,90 Hence, severe malaria is associated with an inflammatory environment that results in a defective adaptive immune response. However, for those that recover from severe malaria, T helper type 1-skewed Tfh cells drive the gradual acquisition of T-bet that is eventually enriched in the atypical memory B-cell compartment.…”

Preparing for re‐entry: is sequential switching the result of recurrent secondary responses?

“…The pathogen‐influenced microenvironment, and in particular cytokines within this milieu, is able to direct isotype switching. To do this, cytokines induce the expression of transcription factors that regulate expression of particular isotypes; furthermore, these transcription factors also form regulatory networks to supress production of inappropriate isotypes 4 . Yet, although one isotype typically dominates the response, multiple IgG subclasses are produced in response to the same pathogen and are postulated to work together to clear the infection 5 , 6 .…”