Macrophage migration inhibitory factor (MIF) is an upstream activator of innate immunity that regulates subsequent adaptive responses. It was previously shown that in macrophages, MIF binds to a complex of CD74 and CD44, resulting in initiation of a signaling pathway. In the current study, we investigated the role of MIF in B cell survival. We show that in B lymphocytes, MIF initiates a signaling cascade that involves Syk and Akt, leading to NF-B activation, proliferation, and survival in a CD74-and CD44-dependent manner. Thus, MIF regulates the adaptive immune response by maintaining the mature B cell population.An established paradigm divides the immunologic response into innate and adaptive components, with critical interactions between the two producing normal immunity or immunopathology. The innate response represents the earliest host response to invasive pathogens by cells such as monocytes/ macrophages, whereas the adaptive response includes the development of antigen-specific responses, antibody production, and immunologic memory. Significant attention is currently focused on the molecules that link innate and adaptive immunity, and that may critically regulate immune responses or the development of inflammatory/autoimmune diseases.CD74 is a non-polymorphic type II integral membrane protein that is expressed on antigen presenting cells including macrophages and B cells. It has a short N-terminal cytoplasmic tail of 28 amino acids, followed by a single 24-amino acid transmembrane region and an ϳ150-amino acid lumenal domain. The CD74 chain was considered initially to function mainly as a major histocompatibility complex class II chaperone, which promotes endoplasmic reticulum exit of major histocompatibility complex class II molecules, directs them to endocytic compartments, prevents peptide binding in the endoplasmic reticulum, and contributes to peptide editing in the major histocompatibility complex class II compartment (1). A small proportion of CD74 is modified by the addition of chondroitin sulfate (CD74-CS), and this form of CD74 is expressed on the surface of antigen presenting cells, including monocytes and B cells. Antibody blocking studies additionally have shown that CD74-CS interacts with CD44, which activates a Src-kinase dependent signaling pathway (2).It was previously shown that macrophage migration inhibitory factor (MIF) 3 binds to the CD74 extracellular domain on macrophages, a process that results in initiation of a signaling pathway (3). MIF accounts for one of the first cytokine activities to have been described (4). MIF promotes monocyte/macrophage activation and is required for the optimal expression of tumor necrosis factor, interleukin-1, and prostaglandin E 2 (5-7). MIF-activated macrophages are more phagocytic and better able to destroy intracellular pathogens, such as Leishmania (8, 9). These activating functions have been verified in MIF knock-out mice (6, 10, 11). The role of MIF in adaptive immunity is less well characterized, but neutralization of MIF using specific anti...
Beyond its established function in hematopoiesis, the bone marrow hosts mature lymphocytes and acts as a secondary lymphoid organ in the initiation of T cell and B cell responses. Here we report the characterization of bone marrow-resident dendritic cells (bmDCs). Multiphoton imaging showed that bmDCs were organized into perivascular clusters that enveloped blood vessels and were seeded with mature B lymphocytes and T lymphocytes. Conditional ablation of bmDCs in these bone marrow immune niches led to the specific loss of mature B cells, a phenotype that could be reversed by overexpression of the antiapoptotic factor Bcl-2 in B cells. The presence of bmDCs promoted the survival of recirculating B cells in the bone marrow through the production of macrophage migration-inhibitory factor. Thus, bmDCs are critical for the maintenance of recirculating B cells in the bone marrow.
Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Previous studies have shown that CLL B lymphocytes express relatively large amounts of CD74 mRNA relative to normal B cells. In the present study, we analyzed the molecular mechanism regulated by CD74 in B-CLL cells. The results presented here show that activation of cell-surface CD74, expressed at high levels from an early stage of the disease by its natural ligand, macrophage migration-inhibition factor (MIF), initiates a signaling cascade that contributes to tumor progression. This pathway induces NF-B activation, resulting in the secretion of IL-8 which, in turn, promotes cell survival. Inhibition of this pathway leads to decreased cell survival. These findings could form the basis of unique therapeutic strategies aimed at blocking the CD74-induced, IL-8-dependent survival pathway.apoptosis ͉ invariant chain B cell chronic lymphocytic leukemia (B-CLL) is characterized by the progressive accumulation of CD5 ϩ B lymphocytes in peripheral blood, lymphoid organs, and bone marrow (1). The hallmark of the disease is decreased apoptosis, resulting in accumulation of these malignant cells. Previous studies have shown that chronic lymphocytic leukemia (CLL) lymphocytes express relatively large amounts of mRNA for CD74, which is the cell-surface form of invariant chain (Ii), as compared with normal B cells (2, 3). CD74 is a nonpolymorphic type II integral membrane protein, which was originally thought to function mainly as an MHC class II chaperone (4). However, CD74 recently was found to play an additional role as an accessory-signaling molecule. In macrophages, CD74 demonstrates high-affinity binding to the proinflammatory cytokine, macrophage migration-inhibitory factor (MIF). MIF binds to the extracellular domain of CD74; this complex is required for MIF-mediated MAPK activation and cell proliferation (5). Moreover, the bacterium Helicobacter pylori was shown to bind to CD74 on gastric epithelial cells and to stimulate IL-8 production (6).In a previous study, we showed that CD74 is involved directly in shaping the B cell repertoire (7, 8) by a pathway leading to the activation of transcription mediated by the NF-B p65/RelA homodimer and its coactivator, TAFII105 (9). NF-B activation is mediated by the cytosolic region of CD74 (CD74-ICD), which translocates to the cell nucleus (10). This signal is terminated by degradation of the active CD74-ICD fragment (11,12). Moreover, we demonstrated recently that CD74 stimulation with an agonistic CD74 antibody leads to NF-B activation, enabling entry of the stimulated B cells into the S phase, an increase in DNA synthesis, cell division, and augmented expression of members of the Bcl-2 protein family. Thus, these findings indicate that surface CD74 functions as a survival receptor (13).In the present study, we sought to determine whether CD74 functions as a survival receptor in B-CLL cells. Our results show that MIF-induced CD74 activation initiates a signaling cascade that results in secr...
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