The last two decades mark a conceptual revolution in immune recognition, switching from one based on engagement of clonal receptor to one that integrates pattern recognition with clonal recognition. The pathogen-associated molecular patterns (PAMP) interacts with several evolutionally conserved pathways, such as Toll-like receptors (TLR) or NOD-like receptors (NLR) to initiate adaptive immune response, although it is now clear that the function of this pattern recognition goes well beyond innate immune protection and initiation of adaptive immunity. In addition to foreign pathogens, the host is also able to respond to injuries through inflammation. Interestingly, one of the signature molecules released during cellular injury, HMGB1, also interacts with TLR. However, this response must be kept under control in order to avoid excessive autoimmune damage following tissue injuries. How the engagement of the same receptor by PAMP would lead to different outcomes than elicited by molecules released during cellular injury remains largely unknown. In the last funding period, we discovered that CD24 on APC negatively regulates T-cell responses to homeostatic cue. In search for molecular mechanisms by which CD24 negatively regulate APC function, we identified two novel CD24 ligands, HMGB1 and SIglec G/10. Based on these discoveries, we hypothesize that CD24 may serve as an important negative regulator for the host response to cellular injury and a molecular mechanism for the negative regulation. This hypothesis will be tested in three sets of experiments. 1). What is the role for CD24-HMGB1 interaction in limiting inflammation, homeostatic proliferation and potential priming of T cells by contents of cellular injuries? We will first study the response of WT and CD24-deficient neonates for their inflammatory response and homeostatic proliferation to HMGB1 stimulation. This will be extended into adult immune competent mice to determine whether CD24 prevent priming of autoreactive T cells specific for antigens released in the context of cellular injury. 2). What is the role for SIglecG/10 in the enhanced homeostatic proliferation? Our preliminary studies indicated that CD24 physically interacts with SIglec 10/G. We will examine the role for SIglecG/10 in APC and T cells in their responses to HMGB1 and determine whether the effect of target mutation with SIglecG and CD24 are interchangeable or synergistic in regulating inflammatory response. 3). What is the molecular mechanism by which CD24 down-regulates inflammatory response initiated by HMGB1? Since SIglecG/10 has ITIM motifs in the cytoplasmic domain that was known to be associated with SHP1 and SHP2, we will test a hypothesis that SIglecG/10 is the signal transducer for CD24-mediated negative regulation. Our proposed studies may reveal a novel pathway for the regulation of host response to cellular injury. Since CD24 defects block the development of autoimmune diseases, our study provides a molecular basis linking inflammation to immunity to cancer or infection without provoking autoimmune diseases.

Public Health Relevance

Our proposed studies may reveal a novel pathway for the regulation of host response to cellular injury. Since CD24 defects block the development of autoimmune diseases, our study provides a molecular basis linking inflammation to immunity to cancer or infection without provoking autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064350-07
Application #
8310166
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dong, Gang
Project Start
2005-01-01
Project End
2012-10-01
Budget Start
2012-09-01
Budget End
2012-10-01
Support Year
7
Fiscal Year
2012
Total Cost
$307,727
Indirect Cost
$104,773
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chen, Guo-Yun; Brown, Nicholas K; Zheng, Pan et al. (2014) Siglec-G/10 in self-nonself discrimination of innate and adaptive immunity. Glycobiology 24:800-6
Liu, Yang (2014) A VISTA on PD-1H. J Clin Invest 124:1891-3
Chen, Guo-Yun; Brown, Nicholas K; Wu, Wei et al. (2014) Broad and direct interaction between TLR and Siglec families of pattern recognition receptors and its regulation by Neu1. Elife 3:e04066
Li, Weiquan; Katoh, Hiroto; Wang, Lizhong et al. (2013) FOXP3 regulates sensitivity of cancer cells to irradiation by transcriptional repression of BRCA1. Cancer Res 73:2170-80
Katoh, Hiroto; Zheng, Pan; Liu, Yang (2013) FOXP3: genetic and epigenetic implications for autoimmunity. J Autoimmun 41:72-8
Zheng, Pan; Chang, Xing; Lu, Qianjin et al. (2013) Cytopenia and autoimmune diseases: a vicious cycle fueled by mTOR dysregulation in hematopoietic stem cells. J Autoimmun 41:182-7
Wu, Qi; Liu, Yu; Chen, Chong et al. (2011) The tuberous sclerosis complex-mammalian target of rapamycin pathway maintains the quiescence and survival of naive T cells. J Immunol 187:1106-12
Wang, Yin; Liu, Yan; Malek, Sami N et al. (2011) Targeting HIF1? eliminates cancer stem cells in hematological malignancies. Cell Stem Cell 8:399-411
Liu, Yang; Chen, Guo-Yun; Zheng, Pan (2011) Sialoside-based pattern recognitions discriminating infections from tissue injuries. Curr Opin Immunol 23:41-5
Chen, Guo-Yun; Tang, Jie; Zheng, Pan et al. (2009) CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323:1722-5

Showing the most recent 10 out of 13 publications