== (A)B cells derived from C57BL/6 and CD74 deficient mice were incubated in the presence or absence of HGF (20 ng/ml) for 8 hr, and quantitative Real Time PCR was performed using primers for MK and -actin. and RPTP are important regulators of the B cell repertoire. These findings could pave the way towards understanding the mechanisms shaping B cell survival, and suggest novel therapeutic strategies based on the blockade of the midkine/RPTP-dependent survival pathway. == Introduction == Adaptive immunity depends on the production and maintenance of a pool of mature peripheral lymphocytes throughout life. In normal individuals, the pool of peripheral lymphocytes is constant in size. The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, survival, and proliferation. Survival factors have been shown to play a critical role in maintaining lymphocyte homeostasis. For many years, the maintenance of peripheral B-cell homeostasis was thought to rely only on two key Mouse monoclonal to VCAM1 elements, BCR tonic signals (e.g., Ig and Syk), and the B cell activating factor, a member of the TNF family (BAFF; BLyS/TALL-1/THANK/zTNF4) (1). Conditional deletion of the BCR on mature B cells results in their apoptosis (2,3). Similarly, ablation of BAFF or its receptor, BAFFR, in mice by either genetic inactivation or using treatments designed to block their action, dramatically reduces the mature B cell pool (1). An additional mechanism that regulates mature B cell survival, and depends on CD74 (invariant chain, Ii) and its ligand, macrophage migration inhibitory factor (MIF), was recently described. CD74 is a non-polymorphic type II integral membrane protein that is expressed on antigen presenting cells, including macrophages and B cells. The CD74 chain was initially thought to function mainly intracellularly as an MHC class II chaperone. A small proportion of CD74 is modified by the addition of chondroitin sulfate (CD74-CS), and this form of CD74 is expressed on UNC569 the surface of antigen presenting as well as other cell types. CD74 UNC569 is expressed as a cell surface complex with CD44 on macrophages (4), B cells (5), and epithelial cells (6). This complex is directly involved in shaping the B cell repertoire (711) by regulating mature B cell survival (5,12,13). It was previously shown that MIF binds to the CD74 extracellular domain on macrophages (14) and on B cells (5). Moreover, we recently demonstrated that CD74 stimulation by MIF recruits the tyrosine kinase receptor, c-Met, to the CD74/CD44 complex and thereby enables the induction of its signaling cascade within the cell (13). This prospects to NF-B activation, entry to the cell cycle, and augmented expression of anti-apoptotic proteins in a CD44-dependent manner. These findings indicate that surface CD74 functions as a survival receptor (5,12,13). In addition, the survival of re-circulating B cells was shown to require the presence of BM-resident dendritic cells (bmDC), which produce MIF in the perivascular BM niches (15). These UNC569 compartments are organized into unique perivascular clusters enveloping selected blood vessels and seeded with mature B and T lymphocytes. Interestingly, both MIF, CD74, and CD44 have been associated with tumor progression and metastasis (1618). CD74 expression has been suggested to serve as a prognostic factor in many cancers, with higher relative expression of CD74 behaving as a marker of tumor progression (19). Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of small, mature CD5+ B-lymphocytes in the peripheral blood, lymphoid organs and bone marrow. In CLL cells, binding of MIF to CD74 initiates a similar signaling cascade that induces NF-B activation and upregulation of TAp63 expression, resulting in the secretion of interleukin 8 (IL-8), which in turn promotes cell survival (20,21). Thus, CD74 expressed on the surface of CLL cells plays a critical role in regulating the survival of these cells. To determine the identities of the molecules whose expression is modulated by CD74, thereby regulating B cell survival, we investigated CD74 target genes. One striking example that we identify here, whose expression is strongly regulated by.
