Adjunct Assistant Professor
Department of Immunology
Roswell Park Cancer Institute
Assistant Professor
Department of Microbiology & Immunology
University at Buffalo
Tel: 716-829-3284
Fax: 716-829-2158
Email:xinlin@buffalo.edu

Current Program

The research projects in my lab are mainly focused on revealing signal transduction pathways that activate NF-B family of transcription factors. NF-B is a family of transcription factors that play critical roles in inflammatory, apoptotic, and immune responses. The function of NF-B family members is regulated through their interactions with a series of cytoplasmic inhibitory proteins termed IB. In unstimulated cells, IB molecules mask the nuclear localization signal (NLS) of NF-B, thereby sequestering NF-B in the cytoplasm. Treatment of cells with various stimuli, such as TNF, IL-1, PMA, and crosslinking T cell receptor (TCR)/CD3 complexes on T cells, initiates signal transduction cascades leading to activation of IB kinase (IKK). Phosphorylation of IB molecules by IKK triggers rapid ubiquitination and proteolysis of IBs in the 26S proteasome complex. The degradation of IB molecules unmasks the NLS of NF-B complexes that rapidly translocate into the nucleus, where NF-B engages cognate B enhancer elements and modulate the transcription of various genes involved in inflammatory, immune, and anti-apoptotic responses. Understanding of the signaling pathways that regulate NF-B activation will provide new therapeutic targets for designing novel agents to cure autoimmune diseases and cancer.

One of the research projects in my lab is to determine how NF-B is activated during T cell activation. Activation of T cells plays a critical role in regulation of immune responses. This process is induced by that MHC molecules on antigen-presenting cells (APC) present antigen peptides to T cell receptors (TCR)/CD3 complexes on the surface of T cells, and by that B7 molecules on APC engage on CD28 receptors on T cells. Co-stimulation of TCR/CD3 and CD28 (CD3/CD28 costimulation) induces a series of signaling transduction events leading to activation of multiple transcription factors including NF-B. However, how CD3/CD28 costimulation activates NF-B remains largely unknown. We have taken molecular, cellular, and genetic approaches to study this mechanism. To determine signaling components involved in CD3/CD28 costimulation induced NF-B activation, we are using somatic mutagenesis methods and combining with cutting-edged FACS analysis to generate mutant T cell lines, which are specifically defected in NF-B activation following CD3/CD28 costimulation. The genes that are required for NF-B activation and mutated in these cell lines will be cloned by genetic complementation. Using this approach, we recently have revealed the critical role of CARMA1, a newly-identified scaffold protein, in TCR-induced NF-B activation. We are currently using knockout and transgenic approaches to study the functional roles of CARMA1 in vivo.

The second project in my lab is to determine how NF-B is activated through stimulation of the members of the TNF receptor family. Tumor necrosis factor alpha (TNF) is a pro-inflammatory cytokine that plays critical roles in inflammation and autoimmune diseases, such as arthritis. Using somatic genetic methods, we have also generated a series of mutant cell lines that contain specific mutations in TNF-induced signaling pathways. Signaling molecules that are specifically involved in this pathway will be characterized and cloned by using retroviral cDNA libraries to complement these mutant cell lines. Currently, we are also developing novel genetic approaches to generate mutant cell lines and clone signaling components in the TNF pathway.
Students and postdoctoral fellows in my lab will receive training to become independent scientists with the cutting-edge knowledge and technology in immunology, molecular and cellular biology.

Key Publications

• Wang, D.; Matsumoto, R.; You, Y.; Che, T.; Lin, X-Y; Gaffen, SL; Lin, X. (2003), CD3-CD28 costimulation-induced NF-B activation is mediated by recruitment of PKC-, Bcl10, and IKK to the immunological synapse through CARMA1, Mol. Cell. Biol. in press
• Che, T.; You, Y.; Wang, D.; Dixit, VM; Lin, X. (2003), MALT1/Paracaspase is a signaling component downstream of CARMA1 and mediates T cell receptor-induced NF-B activation. Submitted to J. Biol. Chem.
• Wang, D., You, Y., Case, S.M., McAllister-Lucas LM, Wang L, DiStefano PS, Nunez, G. Bertin, J. Lin X. (2002), A requirement of CARMA1 in T cell receptor-induced NF-B activation. Nature Immunology, 3(9): 830-5