PROJECT SUIVIIVIARY (See instructions): Our long-term goal is to study the regulation of immune responses under normal and diseased conditions, particularly the invovlement of protein ubiquitination pathway in lymphocyte development, activation, and tolerance inductiion. Cbl-b is composed of an N-terminal tyrosine kinase binding domain, a RING finger, and C-terminal proline-rich sequences. Genetic studies using Cbl-b deficient mice have shown that Cbl-b is critical in T cell activation, and loss of Cbl-b results in increased autoimmunity. Cbl-b functions as RING-type E3 ubiquitin ligase to promote ubiquitin conjugation to critical signaling molelcules and affects their biological functions. More importantly, we showed that Cbl-b is upregulated during T cell anergy induction and controls the tolerigenic process, thus linking protein ubiquitination pathway to the T cell tolerance. We have recently obtained some unexpected and novel observations. Particularly, we found that Cbl-b is involved in the regulation of Foxp3 expression in inducible regulatory T cells (iTregs) via modulating a novel signaling pathway directly acting at the transcriptional regulation of Foxp3 gene. The new findings form a strong basis for us to hypothesize that Cbl-b plays an essential role in controlling immune responses via promoting protein ubiquitination. In this proposal, we wll plan: 1) to investigate the molecular mechanisms by which Cblb E3 ubiquitn ligase regulates Foxp3 gene transcription via modulating Foxo3a-directed gene transcription and to perform genome-wide gene profiling of Tregs to understand the molecular regulation of epigenetic control in Tregs;2) to examine the in vivo function of iTregs in mouse models of autoimmunity and airway inflammation. These studies will significantly advance our understanding ofthe molecular mechanisms governing Foxp3 gene transcription and ITreg-mediated immune regulation. Such knowledge will eventually facilitate the design of novel therapeutic approaches for cancer, autoimmune and allergic diseases.
The immune system has evolved to mount robust responses against invading pathogens, but at the same time is tolerant to self-tissues or self-antigens. The mechanisms governing immune tolerance are not clear. This proposal will study the mechanisms by which the immune responses are properly controlled. Such knowledge will eventually facilitate the design of novel therapeutic approaches for immunological diseases.
|Baca Jones, Carmen; Pagni, Philippe P; Fousteri, Georgia et al. (2014) Regulatory T cells control diabetes without compromising acute anti-viral defense. Clin Immunol 153:298-307|
|Kong, Kok-Fai; Fu, Guo; Zhang, Yaoyang et al. (2014) Protein kinase C-? controls CTLA-4-mediated regulatory T cell function. Nat Immunol 15:465-72|
|Croft, Michael (2014) The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol 26:183-90|
|Baca Jones, Carmen; Filippi, Christophe; Sachithanantham, Sowbarnika et al. (2014) Direct infection of dendritic cells during chronic viral infection suppresses antiviral T cell proliferation and induces IL-10 expression in CD4 T cells. PLoS One 9:e90855|
|Park, Yoon; Jin, Hyung-seung; Aki, Daisuke et al. (2014) The ubiquitin system in immune regulation. Adv Immunol 124:17-66|
|Madireddi, Shravan; Eun, So-Young; Lee, Seung-Woo et al. (2014) Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies. J Exp Med 211:1433-48|
|Boettler, Tobias; Choi, Youn Soo; Salek-Ardakani, Shahram et al. (2013) Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1. J Immunol 191:5026-35|
|Croft, Michael; Benedict, Chris A; Ware, Carl F (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12:147-68|
|Kim, Gisen; Shinnakasu, Ryo; Saris, Christiaan J M et al. (2013) A novel role for IL-27 in mediating the survival of activated mouse CD4 T lymphocytes. J Immunol 190:1510-8|
|Zhao, Yuan; Croft, Michael (2012) Dispensable role for 4-1BB and 4-1BBL in development of vaccinia virus-specific CD8 T cells. Immunol Lett 141:220-6|
Showing the most recent 10 out of 12 publications