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The Choi Laboratory | Email Us
The Abramson Family Cancer Research Institute
421 Curie Boulevard
338 BRB II/III
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Research
T and B lymphocytes are major components of the immune systems higher vertebrates have developed to protect themselves from infectious agents such as bacteria and viruses. AIDS demonstrates the importance of these cells.
The T cell receptor (TCR) triggers pleiotropic (multiple, unrelated) signals leading to the proliferation, activation, anergy (deactivation), or apoptosis (suicide) of T cells. Thus, the TCR is an essential molecule which shapes the way the immune system responds to or tolerates particular foreign entities. However, the quality/quantity of signals in T cells generated by antigens (foreign entities) is also regulated by various other surface molecules on T cells or antigen-presenting cells e.g., the tumor necrosis factor (TNF) and its receptor (TNFR), or cytokines (chemical substances secreted by cells). Hence the overall outcome of alterations in the signaling pathways, which can accommodate the diversity of such responses mediated by the TCR, is very complicated. Therefore, our laboratory has studied how the TNF/TNFR superfamily regulates the pleiotropic signals mediated by TCR-antigen interaction during thymocyte (T cell) development, and the effects this regulation has on immune response.
Some of the TNF/TNFR superfamily members directly affect the antigen-specific T cells (thymocytes). For example, Fas (CD95)- or CD30-mediated signals regulate the induction of apoptosis in some self-reactive T cells. Other TNFR family members, such as TNFRs and 4-1BB, regulate the proliferation and/or apoptosis of T cells in response to various antigens. Therefore, several members of the TNF/TNFR superfamily may independently trigger cell proliferation or death on the same cells. Which and how many members of the superfamily play a role in these processes may depend on various factors, including the properties of different TCR/major histocompatibility complex/antigen complexes or the availability of various protective cytokines.
TNFR superfamily members regulate diverse cellular events by the selective activation of different signal transduction pathways: the caspase cascade, the nuclear factor k B (NF k B) family of transcription factors, and mitogen-activated protein kinases (MAPKs). Caspases are responsible for the proteolytic (protein-splitting) events leading to apoptosis, and NF k B inhibits cell death in many different cell types. MAPKs contribute to activation of activating protein 1, which can regulate growth signals or induce cytokines. Once coordinately activated, these convergent signals may cause cell proliferation, differentiation, or death.
Discrete signaling functions are thought to be initiated by recruiting different types of signal transducers to the TNFR superfamily complexes. Thus far, two major classes of signal transducers have been identified. The first is characterized by a conserved death domain, which enables interaction with TNFR1, Fas (CD95), DR3, or the TRAIL receptors. Clustering of the death domain proteins may lead to the further activation of caspases and subsequently to cell death.
A second class of signal transducers that help orchestrate the functions of the TNFR superfamily members are the TRAF proteins. TRAF proteins interact with the cytoplasmic tails of the TNFR superfamily members (e.g., TNFR1, TNFR2, CD40, CD30, 4-1BB, or LT- b R) and serve as adaptor proteins to recruit downstream signal transducers. To date, six members of the TRAF family have been found. None exhibit enzymatic activity, suggesting they operate solely as signal adaptors.
The TNF/TNFR superfamily also indirectly regulates the antigen-specific response of T cells by modulating the function and survival of antigen-presenting cells such as dendritic cells (DCs). For example, CD40L/CD40 was shown to be critical for antigen-specific T cell priming in vivo . CD40L, expressed on activated T cells, stimulates CD40 on DCs to induce differentiation, cytokine production, and protection from apoptosis in these cells. We have cloned a new member of the TNF family, TRANCE, which is highly expressed on activated T cells. The TRANCE receptor (TRANCE-R) is predominantly expressed on mature DCs, and the TRANCE/TRANCE-R interaction enhances DC survival, thereby promoting DC-mediated T cell proliferation. Moreover, TRANCE plays a critical role in the regulation of antigen-specific T cell responses during viral infections.
Our studies have elucidated some of the mechanisms by which various TNF/TNFR family members and their signal transducers regulate the various antigen-specific responses of T cells, either directly or indirectly. Further studies will be required to understand at the molecular level how these pleiotropic signals generated by the antigen receptors and other molecules such as the TNF/TNFR family members are coordinated to induce the proliferation, activation, anergy, or apoptosis of T cells that determines the ultimate T cell fate leading to successful immune response or tolerance. This project is supported in part by a grant from the National Institutes of Health.
As mammals develop, they experience numerous transformations in weight and size. Throughout these changes, bones provide firm support for the body, mechanical integrity of movement, and connection with pathways associated with mineral homeostasis. In addition, bone is an indispensable connective tissue and the primary site for hematopoiesis (the formation of blood and blood cells). Osteoblasts and osteoclasts provide bones with the adaptability to survive the stresses they face during a lifetime. Osteoblasts are responsible for bone formation; osteoclasts are involved in the bone removal, or resorption, process.
Osteoclasts are generated from hematopoietic precursors located in bone marrow. TRANCE is an essential factor for osteoclast development. For example, TRANCE-deficient mice do not develop osteoclasts and fail to resorb bones, leading to the severe form of osteopetrosis. In addition to its role in the development of osteoclasts from precursor cells, TRANCE plays a critical role in activation and survival of mature bone-resorbing osteoclasts. An important direction of our work, therefore, will be to determine the molecular pathways leading to the differentiation of mature osteoclasts from precursor cells by TRANCE and also the principles leading to the activation and survival of mature osteoclasts by TRANCE.
If there is a disruption in the relationship between osteoclasts and osteoblasts during remodeling of bones in vivo, the detrimental consequences include osteoporosis. Occurring predominantly in postmenopausal women and elderly men, osteoporosis results in a reduction of the amount of bone or atrophy of skeletal tissue. Osteoporosis leaves bones fragile and thin; they break easily under minimal amounts of stress. Regardless of its etiology, osteoporosis is a product of enhanced bone resorption as opposed to bone formation. Since osteoclasts are the only resorptive cells of bone, understanding their development and activation may lead to advances in the treatment and prevention of osteoporosis. |
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