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

No abstract

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.