The DZ is proximal to the T cell area and contains rapidly dividing B cells called centroblasts that express little or no surface immunoglobulin. are thymus-dependent. GC B cells require ongoing survival and proliferation signals that depend on CD154-CD40 signaling (9). CD154, a member of the TNF family, is usually inducibly expressed on the surface of CD4 T lymphocytes, whereas its ligand, CD40, is usually constitutively present on B lymphocytes (examined in ref. 10). T cellCdependent GCs begin with the individual activation of T and B cells by antigen (11). In secondary lymphoid tissues, binding of antigen modifies B cell chemotaxis, resulting in migration toward the T cell zone (12), where cognate T cellCB cell conversation expands both Mavoglurant lymphocyte populations. Soon afterward, activated T and B cells emigrate from T cell areas into the reticula of follicular dendritic cells (FDCs) that define the B cell follicle (Physique ?(Figure1).1). The immigrant B lymphocytes proliferate in the FDC reticulum to generate nascent GCs and, Mavoglurant in the process, acquire unique Rabbit polyclonal to ATF1.ATF-1 a transcription factor that is a member of the leucine zipper family.Forms a homodimer or heterodimer with c-Jun and stimulates CRE-dependent transcription. phenotypes, including expression of the CD69 activation antigen and several differentiation markers, including CD38 and CD27. Remarkably, human CD38+ GC B cells can also express variable levels of CD154, especially under conditions of chronic activation (13, 14), and appear to have the capacity for continued self-activation. Open in a separate window Physique 1 Potential cellular targets for passive CD154 antibody to interrupt thymus-dependent GC and antibody responses. Antigen-specific T and B lymphocytes meet at the interface of T and B cell zones (follicles) in secondary lymphoid tissues (I). CD40-CD154 interaction results in the local proliferation of both lymphocyte types. Following clonal expansion, a portion of activated T and B cells, prompted by CD40-CD154 signaling, migrate into the follicle to initiate the GC reaction (II). In GCs, B cells proliferate and activate AID-dependent SHM and CSR. Other clonally related B lymphocytes are retained in extra-follicular sites and differentiate Mavoglurant into antibody-forming cells (AFCs), or plasmacytes (III). These transient AFCs do not express AID and do not support CSR and SHM. In GCs, centroblasts proliferate in the DZ, migrate to the LZ as centrocytes, present antigen to LZ T cells, and receive signals that direct either their exit from your GC or return to the DZ (IV). Centrocytes that do not receive survival signals pass away by apoptosis. Active GCs require continuous CD40-CD154 signaling; these signals may symbolize homotypic conversation between CD40+CD154+ centroblasts or heterotypic signals between CD40+ centrocytes and CD154+CD4 T cells. Determined B cells exit the GC (V) to enter the memory or long-lived plasmacyte compartments. Grammer et al. (17) observe that passive anti-CD154 reduces the numbers of IgD+CD38+ GC precursors (I and II) and CD38bright plasmacytes (III and V) but has little effect on circulating GC (IgDCCD38+) cells (IV). The primary effect(s) of CD154 antibody in SLE patients may be to interrupt the early initiation (I) and/or migrations actions (II) of the GC reaction. GCs become polarized into histologic dark and light zones (DZ, LZ). The DZ is usually proximal to the T cell area and contains rapidly dividing B cells called centroblasts that express little or no surface immunoglobulin. The more distal LZ contains the bulk of the activated FDC network, antigen-specific CD4 T cells, and nondividing B cells known as centrocytes. Centrocytes express surface immunoglobulin and are thought to be the progeny of DZ centroblasts. In turn, selected centrocytes likely reenter the DZ and regain the centroblast form. The enzyme AID (activation-induced cytidine deaminase) drives both somatic hypermutation (SHM) and immunoglobulin class switch recombination (CSR) in GC B cells (15). SHM introduces point mutations and occasional small deletions into the V(D)J regions of transcriptionally active immunoglobulin genes. Mutations are probably launched in centroblasts and accumulate during repeated rounds of centroblast/centrocyte migration between the DZs and LZs (Physique ?(Figure1).1). Intense selection for higher-affinity mutants establishes GCs as foci of fast somatic antibody and evolution affinity maturation. CSR means that mutated,.