Molecular mechanisms regulating differentiation and...
In healthy 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 the correct size of lymphocyte populations.B cells represent a critical arm of the adaptive immune system and under normal circumstances, provide long lasting immunity to a wide range of pathogens. The maintenance of peripheral B-cell homeostasis relies on three key elements (1) B cell receptor (BCR) tonic signals (2) the B cell activating factor, belonging to the TNF family (3) Our studies characterized a novel arm of receptors controlled by CD74 (invariant chain, Ii) and its ligand, macrophage migration inhibitory factor (MIF) and their downstream molecules hepatocyte growth factor (HGF) and midkine (MK). We showed that MIF binding to CD74 induces a signaling pathway that involves the Syk tyrosine kinase and the PI3K/Akt pathway, induction of CD74 intramembrane cleavage, and the release of the CD74 intracellular domain (CD74-ICD). CD74-ICD translocates to the nucleus where it induces activation of transcription mediated by the NF-B p65/RelA homodimer and its co-activator, TAFII105, resulting in regulation of transcription of genes that control B cell proliferation and survival.
Relevant Projects
The role of CD74 in transcription regulation
The role of CD74 in the development of early progenitor cells in the BM
Control of B cell survival in disease
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world; characterized by the progressive accumulation of small, mature CD5+ B lymphocytes in the peripheral blood, lymphoid organs and bone marrow (BM). Unlike other leukemias, the main feature of the disease is decreased apoptosis, resulting in the pathologic accumulation of these malignant cells.
Our lab characterized CD74 as a survival receptor expressed on these leukemic cells. In our search for genes whose expression is modulated by CD74, we identified the cell surface molecule CD84.
CD84 is expressed on all hematopoietic cells as well as on CLL cells, where its expression is elevated from the early stages of the disease. We showed that activation of CD84 leads to survival of CLL cells in vitro and in vivo. Blocking CD84 using anti-CD84 blocking antibodies, which was generated in our lab, induced CLL cell death.
Our lab is currently studying the role of CD84 in mediating interaction of CLL cells with their survival supporting microenvironment.
Relevant Projects
The interplay between chronic lymphoid leukemia (CLL) and the microenvironment via CD84
CD84 regulates the interaction of CLL cells with their microenvironment and the ECM
Exploring the role of Slam family members in survival of multiple myeloma
X-linked lymphoproliferative disease (XLP) is a rare immune disorder commonly triggered by infection with Epstein-Barr virus. XLP is clinically characterized by three major phenotypes: fulminant infectious mononucleosis (FIM) (50%), B cell lymphomas (20%), or dys-gammaglobulinemia (30%). Most patients with XLP die by the age of 40 and more than 70% of patients die before the age of ten. Mutations in the SAP, a signaling adaptor molecule, underlie in most cases of familial XLP.
Our study aims to determine the mechanism that governs the B cell repertoire and function in XLP patients. In these experiments, we analyze B cells derived from peripheral blood (PB) of XLP patients and healthy human control subjects. In parallel, to address the question of whether SAP plays a role in B-cell function we are also examining B cells derived from SAP deficient mice.
Overall, our findings illuminate several interesting aspects of signaling and function into the pathology of the XLP disease. Moreover, it raises the possibility that in the future manipulation of SAP-mediated signaling pathways may have therapeutic benefits.
Relevant Projects:
B cell-T cell signaling through SAP is essential for the maintenance of peripheral B cell populations
T cell homeostasis in health and autoimmunity
The surveillance of the body for foreign antigens is a critical function of the immune system. Lymphocytes migrate from the blood into tissues and secondary lymphoid organs, and return to the blood via lymph vessels and the thoracic duct. The majority of lymphocytes are capable of tissue-selective trafficking (homing), recognizing organ-specific adhesion molecules on specialized endothelial cells. Our studies focus on regulation of the immune response in health and disease.
The surveillance of the body for foreign antigens is a critical function of the immune system. Lymphocytes migrate from the blood into tissues and secondary lymphoid organs, and return to the blood via lymph vessels and the thoracic duct. The majority of lymphocytes are capable of tissue-selective trafficking (homing), recognizing organ-specific adhesion molecules on specialized endothelial cells. Our studies focus on regulation of the immune response in health and disease. We analyzed chemokine-induced pathways that restrict homing of specific subsets of immune cells and regulate differentiation to regulatory and effector T cells. These pathways can fine-tune the immune response at specific lymphoid and peripheral tissues in health. However, the system can go awry, in several ways. The body can mistakenly attack itself in autoimmune diseases, or those cells can dramatically overreact, as occur in asthma. Our results show that these chemokine-induced pathways can be utilized in suppression of these uncontrolled inflammatory responses and in the future might be applied in treatment of inflammatory diseases.
Relevant Projects:
CD151 regulates T cell migration in health and inflammatory bowel disease
The CCR2 chemokine receptor as a direct regulator of CD4+ T cell responses
[Read more] about T cell homeostasis in health and autoimmunity