We next focused on identifying subdomains of the Fas Ligand cytoplasmic tail that are critical for mediating costimulation. Despite the normal surface expression and killing mediated by mutated Fas Ligand lacking amino acids 45-54 in the proline-rich region of the Fas Ligand cytomplasmic domain, this mutant fails to costimulate, inhibiting Akt and Erk1/2 activation and antigen-specific CD8+ T cell proliferation. We further demonstrate that two conserved casein kinase I binding sites in the Fas ligand cytoplasmic domain are critical for Fas ligand costimulation by regulating NFAT activation. These results comprise the first mechanistic analysis of a newly emerging group of costimulators, the TNF family. Our work sheds light on the molecular understanding of Fas ligand as a double-edged immunomodulator, and helps to resolve the question of how one molecule can mediate discrete biological consequences in the immune system.

Fas Signaling is focused on the signaling mechanisms and biology of the prototypic death receptor Fas, also called CD95 or APO-1. The chapters of this book cover, besides the well recognized apoptosis-related functions of Fas, its emerging role as a proinflammatory cytokine and as an inducer of alternative forms of cell death. Fas Signaling aims to provide the reader with an up-to-date survey of the various aspects of Fas biology and the open questions of the field are addressed. This title is intended for Ph.D and post-doctoral students starting to work in the field, but is also useful for everyone with an interest in the biology of this exciting molecule.

Binding of Fas Ligand (FasL) to the Fas receptor triggers apoptosis of the receptor-bearing cell, which plays a pivotal role for homeostasis of the immune system and during acute immune responses. Similar to other TNF family members, the intracellular FasL domain is able to transmit signals into the FasL-bearing cell ("reverse signaling"). Recently, we have described a Notch-like proteolytic processing of FasL by the proteases ADAM10 and SPPL2a, which leads to the release of the intracellular domain (FICD) into the cytoplasm. Following the cleavage event, FICD translocates to the nucleus and influences gene transcription. To study the physiological importance of FasL reverse signaling in vivo on the level of the endogenous proteins, we have established a knockout/knockin mouse model in which wildtype FasL was replaced with a deletion mutant lacking the intracellular portion (FasL Intra). Our ex vivo and in vivo findings demonstrate that FasL reverse signaling is a negative modulator of certain immune responses. It is tempting to speculate that FasL reverse signaling might be a fine-tuning mechanism to prevent autoimmune diseases.

We have investigated a possible role of Fas ligand (FasL) in reverse signaling to mediate cell survival and growth signals through its intracellular proline-rich domain to protect FasL-expressing breast cancer cells from cell death. We have generated expressing constructs containing either a wild-type or the cytoplasmic proline-rich domain-deletion mutant cDNAs of FasL and transfected them into NIH 3T3 cells. We found that the cells expressing the wild-type FasL are more resistant to Fas-induced cell death than the mutant, suggesting that the cytoplasmic proline-rich domain of FasL indeed promote cell survival. We also generated bacteria-expressed GST-FasL fusion proteins and used these proteins to identify proteins that physically interact with the cytoplasmic domain of FasL. Two protein bands from 35S-Methioline-labled 3T3 cell lysates were found to specifically bind to FasL. We are currently characterizing these proteins. These results suggest a novel function of FasL in promoting survival and growth of breast cancer cells. The complete understanding of function and mechanism of FasL in tumor cells is necessary for developing effective diagnostic and therapeutic reagents to treat breast cancer patients.

Completely revised and expanded, this second edition of The Cytokine FactsBook is the most up-to-date reference manual available for all current well-characterized interleukins, cytokines, and their receptors. An additional 52 cytokines are included, doubling the number of entries from the previous edition. The key properties of each cytokine are described and presented in a very accessible format with diagrams for each of the receptors. The Cytokine FactsBook includes free online access to the regularly updated Cytokine Webfacts. Cytokine Webfacts is a web-based comprehensive compendium of facts about cytokines and their receptors that includes a variety of data representations, such as text, signal pathway diagrams and 3D images. This exciting resource is integrated into other databases via hypertext links to provide a unique network, and contains a web-enabled version of RasMol for viewing structures.

There have been tremendous strides in cellular transplantation in recent years, leading to accepted practice for the treatment of certain diseases, and use for many others in trial phases. The long history of cellular transplantation, or the transfer of cells from one organism or region of the body to another, has been revolutionized by advances in stem cell research, as well as developments in gene therapy. Cellular Transplants: From Lab to Clinic provides a thorough foundation of the basic science underpinning this exciting field, expert overviews of the state-of-the-art, and detailed description of clinical success stories to date, as well as insights into the road ahead. As highlighted by this timely and authoritative survey, scale-up technologies and whole organ transplantation are among the hurdles representing the next frontier. The contents are organized into four main sections, with the first covering basic biology, including transplant immunology, the use of immunosuppressive drugs, stem cell biology, and the development of donor animals for transplantation. The next part looks at peripheral and reconstructive applications, followed by a section devoted to transplantation for diseases of the central nervous system. The last part presents efforts to address the key challenges ahead, such as identifying novel transplantable cells and integrating biomaterials and nanotechnology with cell matrices. Provides detailed description of clinical trials in cell transplantation Review of current therapeutic approaches Coverage of the broad range of diseases addressed by cell therapeutics Discussion of stem cell biology and its role in transplantation