Anergy, a condition in which cells persist in the periphery but are unresponsive to antigen, is responsible for silencing many self-reactive B cells. Loss of anergy is known to contribute to the development of autoimmune diseases, including systemic lupus erythematosus and type 1 diabetes. Multiple transgenic mouse models have enabled the dissection of mechanisms that underlie anergy, and recently, anergic B cells have been identified in the periphery of wild-type mice. Heterogeneity of mechanistic concepts developed using model systems has complicated our understanding of anergy and its biological features. In this Review, we compare and contrast the salient features of anergic B cells with a view to developing unifying mechanistic hypotheses that explain their lifestyles.The generation of B cells occurs throughout life and proceeds through several distinct stages and checkpoints (FIG. 1). After birth, B-cell generation occurs in the bone marrow, where cells progress through pro-B-cell and pre-B-cell stages of development. At the next stage (as immature B cells), they acquire antigen specificity by virtue of expression of a functional Bcell receptor (BCR); this is also the first key specificity checkpoint in B-cell development. Cells that successfully traverse this phase enter the periphery as transitional B cells.The ability of the adaptive immune system to provide protection against pathogens requires a diverse BCR repertoire that can recognize a broad range of foreign proteins. Diversity is generated early in development by random rearrangement of immunoglobulin genes. This inevitably results in the genesis of receptors that recognize self antigens. It is estimated that 75% of human early immature B cells are self-reactive 1 . About a third of these self-reactive immature B cells are purged from the repertoire by receptor editing, wherein renewed immunoglobulin gene rearrangement generates a new light chain to pair with the existing immunoglobulin heavy chain in an anthropomorphic effort to generate a non-self-reactive © 2007 Nature Publishing Group Correspondence to J.C.C. cambierj@njc.org. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH Public Access Author ManuscriptNat Rev Immunol. Author manuscript; available in PMC 2013 July 17. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript BCR 2,3 . Failing this, these B cells are deleted by apoptosis 4 . Despite these mechanisms of central tolerance, many self-reactive B cells escape to the periphery where they are silenced by an induced state of unresponsiveness known as anergy (BOX 1). Anergy can be viewed as nothing more than the state of lethargy that ensues when B cells mount a normal initial response to antigen but fail to receive secondary signals that sustain their activation. Paradoxically, the maintenance of anergy requires chronic binding of antigen and signal transduction, yet the stimulation of unoccupied receptors fails to trigger signal transduction pathways that are...

NF‐Y binds a CCAAT motif found in many eukaryotic polymerase II‐dependent promoters. In the HLA‐DRA promoter it has been demonstrated that stereo‐specific alignment between this motif and the upstream elements X1 and X2 is required for activation. To study the underlying mechanism for this requirement, a panel of transfected cell lines that maintained integrated, wild‐type and mutant promoters were analyzed by in vivo genomic footprinting. Cell lines harboring a mutated CCAAT element exhibited a loss of interactions at the CCAAT site, as expected, and no transcriptional activity. Most importantly, mutation of the CCAAT sequence nearly abolished in vivo binding at the X1 and X2 sites, while mutations of X1 and X2 had little effect on CCAAT box binding. However, X1 and X2 binding was interdependent. In vitro, X1 binding activities are known to be stabilized by NF‐Y binding. Interaction between NF‐Y and X box binding proteins was demonstrated by reciprocal co‐immunoprecipitation in the absence of DNA and co‐affinity purification in the presence of DNA. Collectively, these studies indicate that occupancy of the CCAAT element represents an early event affecting other protein‐DNA interactions and suggest that NF‐Y stabilizes and interacts with X box factors to mediate this function. These findings may represent a common theme among promoters containing a CCAAT element.

CD8 engagement is believed to be a critical event in the activation of naive T cells. In this communication, we address the effects of peptide-MHC (pMHC)/TCR affinity on the necessity of CD8 engagement in T cell activation of primary naive cells. Using two peptides with different measured avidities for the same pMHC-TCR complex, we compared biochemical affinity of pMHC/TCR and the cell surface binding avidity of pMHC/TCR with and without CD8 engagement. We compared early signaling events and later functional activity of naive T cells in the same manner. Although early signaling events are altered, we find that high-affinity pMHC/TCR interactions can overcome the need for CD8 engagement for proliferation and CTL function. An integrated signal over time allows T cell activation with a high-affinity ligand in the absence of CD8 engagement.

No abstract

Ab-secreting plasma cells (PCs) are the effectors of humoral immunity. In this study, we describe regulation of autoreactive B cells specific for the ribonucleoprotein Smith (Sm) at an early pre-PC stage. These cells are defined by the expression of the PC marker CD138 and normal levels of CD19 and B220. They are present at a high frequency in normal mouse spleen and bone marrow, are Ag dependent, and are located predominantly along the T cell-B cell border and near bridging channels. Anti-Sm pre-PCs also occur at a high frequency in nonautoimmune mice and show additional phenotypic characteristics of PC differentiation. However, while some of these pre-PCs are Ab-secreting cells, those specific for Sm are not, indicating regulation. Consistent with this, anti-Sm pre-PCs have a higher turnover rate and higher frequency of cell death than those that do not bind Sm. Regulation of anti-Sm pre-PCs occurs upstream of the transcriptional repressor, B lymphocyte-induced maturation protein-1, expression. Regulation at this stage is overcome in autoimmune MRL/lpr mice and is accompanied by an altered B lymphocyte stimulator receptor profile. These data reveal a new B cell tolerance checkpoint that is overcome in autoimmunity.