T cell–specific NFAT2 deletion results in reduced CXCR5+ follicular regulatory T cells, leading to uncontrolled germinal center responses and humoral autoimmunity.

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RelB is an unusual member of the NF-〉 transcription factor family that acts as both a transcriptional activator as well as a repressor of NF-〉-dependent gene expression. Although RelB promotes gene expression when it associates with p50/NF-〉1 or p52/NF-〉2, the precise molecular mechanisms through which it represses NF-〉 remain unclear. To examine this inhibitory function in more detail, we employed reporter gene assays and found that RelB represses at the level of RelA. Furthermore, electrophoretic mobility shift analysis revealed that in vitro translated RelB impaired the DNA binding activity of RelA and that overexpressed RelB significantly reduced tumor necrosis factor-␣-induced RelA activity in murine embryonic fibroblasts. Intriguingly, this inhibitory effect was due to the formation of RelA⅐RelB heterodimers that were unable to bind to B sites in vitro strongly suggesting that these newly described NF-〉 dimers cannot bind DNA. Expression pattern analysis revealed that RelA⅐RelB heterodimers appeared at relatively low levels in both lymphoid and non-lymphoid cells. However, the presence of these complexes increased following stimulation with phorbolesters or lipopolysaccharide or by overexpression of constitutively active IK⌲␤. Functional characterization of RelA⅐RelB heterodimers in NIH3T3 murine embryonic fibroblasts revealed that they are not regulated by I〉 proteins and are located in both the cytoplasm and the nucleus. Taken together, our findings demonstrate that sequestration of RelA in transcriptionally inactive RelA⅐RelB complexes provides a molecular mechanism that may explain the repressive role of RelB on NF-〉-dependent gene expression.

The B cell‐associated surface molecule CD40 plays a key role in T cell‐dependent B cell maturation, as individuals with defects in either CD40 or its ligand are impaired in immunoglobulin isotype class switching and germinal center formation. CD40 signaling activates downstream effectors, including the tyrosine protein kinase, Lyn, the phosphatidylinositol‐3‐kinase (PI‐3 kinase), and the transcription factor, NF‐kappa B. In this study, we demonstrate that stress‐activated protein kinases (SAPK) are activated after CD40 cross‐linking on various B cell lines or human tonsillar B cells. The activation is rapid and transient and is mediated through a cyclosporin A‐insensitive pathway. Furthermore, this signaling pathway appears not to rely on protein kinase C. While CD40 ligation strongly activates the SAPKs (up to 25‐fold), it does not affect members of the mitogen‐activated protein kinase family (MAPK; ERK1 and ERK2). Consistent with these data, CD40 signals up‐regulate c‐jun but not c‐fos mRNA and alter the transcription factor ATF2 but not the Raf‐1 protein. In summary, CD40 signaling preferentially induces SAPK but not MAPK.

Key Points Novel GM-CSF signaling pathways through IFN-γR/IRF-1 and AKT/mTOR provide monocyte licensing for suppressor function. Only licensed but not fresh Ly-6Chigh murine or human CD14+ monocytes secrete nitric oxide or IDO for T-cell suppression.

RelB is an unusual member of the Rel/NF-kB family of transcription factors which are involved in oncogenic processes. Due to a relaxed control by the IkBs, the cytosolic NF-kB inhibitors, RelB is constitutively expressed in the nuclei of lymphoid cells. We show here that RelB is inducibly degraded upon activation of T cells in a fashion similar to the IkBs. However, RelB degradation di ers from that of IkBs since it is not induced by TNFa but only by T cell receptor or TPA/ ionomycin stimulation. Moreover, RelB degradation occurs in three steps: (i) after stimulation RelB is rapidly phosphorylated at amino acids Thr84 and Ser552 followed by (ii) an N-terminal cut and, ®nally, (iii) the complete degradation in the proteasomes. Since mutation of the two phosphoacceptor sites to non-acceptor sites abolished RelB phosphorylation in vivo and led to the stabilization of the mutated RelB DM , site-speci®c phosphorylation appears to be a necessary prerequisite for RelB degradation. RelB is a crucial regulator of NFkB-dependent gene expression. Thus, the signal-induced degradation of RelB should be an important control mechanism of NF-kB activity. Oncogene (2001) 20, 8142 ± 8147.

Engagement of the antigen receptor on murine immature B cells leads to growth arrest followed by apoptosis. Concomitant signaling through CD40 sustains proliferation and rescues the cells from apoptosis. We show here that cross‐linking CD40 stimulates the expression of A1, a member of the anti‐apoptotic Bcl‐2 family, in primary murine B lymphocytes. CD40‐dependent stimulation of A1 was confirmed in WEHI 231 cells, an immature murine B cell lymphoma line. We transduced WEHI 231 cells with a bicistronic recombinant retroviral vector coding for A1 and a chimeric selection marker comprising the enhanced yellow fluorescent protein and the zeocin resistance protein. A1‐transduced WEHI 231 cells showed a significant higher survival rate after engagement of the antigen receptor. In contrast, constitutive expression of A1 did not abrogate anti‐IgM‐induced c‐myc down‐regulation. Consistant with this, A1 did not release anti‐IgM‐induced cell cycle arrest. Our data indicate that CD40‐stimulated A1 expression permits WEHI 231 cells to survive in the presence of anti‐IgM antibodies and suggests a protective role for A1 in antigen receptor‐mediated apoptosis in B cells.

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