B-lymphocyte quiescence, tolerance and activation as viewed by global geneexpression profiling on microarrays

Sell-tolerance is achieved by deleting or regulating self-reactive lymphocy tes at a series of cellular checkpoints placed at many points along the dev elopmental pathways to plasma cells and effector T cells. At each checkpoin t, what are the molecular pathways that determine whether a lymphocyte rema ins quiescent, begins dividing, differentiates or dies? In splenic B cells, the decision between quiescence, tolerance by anergy, and activation provi des a tractable setting to explore these issues by global, gene expression profiling on DNA microarray;. Here we discuss the application of microarray s to illuminate a set of cell fate decisions that appear to be determined b y summation of numerous small changes in expression of stimulatory and inhi bitory genes. Many genes with known or predicted inhibitory functions are h ighly expressed in naive, quiescent B cells, notably the signal inhibitor S LAP and DNA-binding proteins of the Kruppel family (LKLF, BKLF, GKLF), Tsc- ZZ, GILZ, Id-3, and GADD45. Activation of naive B cells, triggered by acute binding of antigen to the B-cell receptor, involves a rapid decrease in ex pression of these inhibitory genes. Promitotic genes are induced in paralle l, including c-myc, LSIRF/IRF4, cyclin D2, Egr-1 and Egr-2, as are the anti -apoptotic gene Al and genes for the T-cell-attracting chemokines MIP-1 alp ha and beta. B-cell tolerance through the process of anergy, induced by chr onic binding of self antigen, maintains expression of the inhibitory genes found in quiescent B cells and induces an additional set of inhibitory gene s. The latter include inhibitors of signaling - CD72, neurogranin, pcp4 - a nd additional inhibitors of gene expression such as SATB1, MEF2C, TGIF and Nab-2. The effects of tolerance, the immunosuppressive drug FKS06 and other modulators of calcium or MAPK signaling allow individual gene responses to be linked to different signal transduction pathways. The global molecular profiles obtained illustrate how quiescence and anergy are actively maintai ned in circulating B cells, how these states are switched to clonal expansi on and how they could be better emulated by pro-tolerogenic drugs.