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CpG DNA redirects class-switching towards "Th1-like" Ig isotype production via TLR9 and MyD88

Unmethylated CpG‐containing DNA plays a critical role in immunity via the augmentation of Th1 but suppression of Th2 T cell responses. We describe here that CpG motifs also redirect isotype production by murine B cells to Th1‐like Ig isotypes (IgG2a, IgG2b, and IgG3) while suppressing Th2 isotypes (IgG1 and IgE). Using genetically mutant B cells, we find that the IgG2a, IgG2b and IgG3 isotypes are transcriptionally regulated via the promotion of class‐switching, in a manner critically dependent upon TLR9 and MyD88. Thus, CpG DNA redirects Ig isotype production by regulating the specificity of class‐switch recombination.

Active Inhibition of Plasma Cell Development in Resting B Cells by Microphthalmia-associated Transcription Factor

B cell terminal differentiation involves development into an antibody-secreting plasma cell, reflecting the concerted activation of proplasma cell transcriptional regulators, such as Blimp-1, IRF-4, and Xbp-1. Here, we show that the microphthalmia-associated transcription factor (Mitf) is highly expressed in naive B cells, where it antagonizes the process of terminal differentiation through the repression of IRF-4. Defective Mitf activity results in spontaneous B cell activation, antibody secretion, and autoantibody production. Conversely, ectopic Mitf expression suppresses the expression of IRF-4, the plasma cell marker CD138, and antibody secretion. Thus, Mitf regulates B cell homeostasis by suppressing the antibody-secreting fate.

Coordination of NF-κB and NFAT Antagonism by the Forkhead Transcription Factor Foxd1

Forkhead transcription factors play critical roles in the maintenance of immune homeostasis. In this study, we demonstrate that this regulation most likely involves intricate interactions between the forkhead family members and inflammatory transcription factors: the forkhead member Foxd1 coordinates the regulation of the activity of two key inflammatory transcription factors, NF-AT and NF-κB, with Foxd1 deficiency resulting in multiorgan, systemic inflammation, exaggerated Th cell-derived cytokine production, and T cell proliferation in autologous MLRs. Foxd1-deficient T cells possess increased activity of both NF-AT and NF-κB: the former correlates with the ability of Foxd1 to regulate casein kinase 1, an NF-AT inhibitory kinase; the latter with the ability of Foxd1 to regulate Foxj1, which regulates the NF-κB inhibitory subunit IκBβ. Thus, Foxd1 modulates inflammatory reactions and prevents autoimmunity by directly regulating anti-inflammatory regulators of the NF-AT pathway, and by coordinating the suppression of the NF-κB pathway via Foxj1. These findings indicate the presence of a general network of forkhead proteins that enforce T cell quiescence.

Restraint of B Cell Activation by Foxj1-Mediated Antagonism of NF-κB and IL-6

The forkhead transcription factor Foxj1 inhibits spontaneous autoimmunity, in part by antagonizing NF-κB activation in T cells. We demonstrate here that Foxj1 also inhibits humoral immune responses intrinsically in B cells; Foxj1 deficiency in B cells results in spontaneous and accentuated germinal center formation, associated with the development of pathogenic autoantibodies and accentuated responses to immunizations—all reflecting excessive activity of NF-κB and its target gene IL-6, and correlating with a requirement for Foxj1 to regulate the inhibitory NF-κB component IκBβ. Thus, Foxj1 restrains B cell activation and the maturation of humoral responses, demonstrating a critical role for at least this forkhead transcription factor in the regulation of B lymphocyte homeostasis.