Cellular immunity is mediated largely through T-cells which interact with foreign antigens presented in the context of classical MHC class I, class II and non-classical MHC molecules. The main goal is to understandthe structuralbasisfor T-cell recognition and T-cell signaling and the interplay with other key cellular antigen receptors in the innate immune system, such as Toll-like receptors (TLRs).Furthermore, the recent exciting discovery of an adaptive immune system in jawless vertebrates that uses Variable Lymphocyte Receptors(VLRs) with Leu-rich repeats,as in TLRs, for antigen recognition, but rearranges them as forTCRs and antibodies to create diversity,provides an important link for the evolution of antigen receptors in the immune system. Novelco-stimulatory receptors for op and 78 T-cell activation and differentiation will be pursued with Junctional Adhesion Molecule (JAML) for 78 T-cell activation and novel T-cell Ig and Mucin (TIM) receptors for Th1/Th2 commitment of CD4+ T-cells. The long term goal is to assemble a complete TCR signaling complex that includes the a|3TCR, pMHC, CDSy, 8, e,? and CDS. The ap1,78 and pre-T-cell receptorsall recognize and interact with CDS, but their interactions differ as the components of the various TCR types are not conserved. The CDScomponents will be studied independently and as complexes with the different TCRs. In addition, the CDSco-receptor interaction will be investigated as TCR-pMHC-CDS complex. Many key questions will be addressed including the structuralprinciples of TCR/MHC recognition that define MHC restriction, what structural features are correlatedwith alloreactivity and autoimmunity, whether CDS interactswith both pMHC and TCR, and the major question concerning the structure, stoichiometry and function of the T-cell signaling complex.This later goal is ambitious ,but represents the only way to probe the structural basis of T-cell signaling. The benefits from this work include an increased understanding of the adaptive and innate immune response to microbial pathogens and elucidation of the structuralbasis of tolerance, autoimmunity, alloreactivity, cross-reactivity and host versus graft disease intransplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI042266-14
Application #
7997242
Study Section
Special Emphasis Panel (NSS)
Program Officer
Leitner, Wolfgang W
Project Start
1998-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
14
Fiscal Year
2011
Total Cost
$626,917
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Collins, Bernard C; Nakahara, Hiro; Acharya, Sharmistha et al. (2017) Crystal structure of an anti-idiotype variable lymphocyte receptor. Acta Crystallogr F Struct Biol Commun 73:682-687
Das, Nabanita; Dewan, Varun; Grace, Peter M et al. (2016) HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia. Cell Rep 17:1128-1140
Baranczak, Aleksandra; Liu, Yu; Connelly, Stephen et al. (2015) A fluorogenic aryl fluorosulfate for intraorganellar transthyretin imaging in living cells and in Caenorhabditis elegans. J Am Chem Soc 137:7404-14
Lockner, Jonathan W; Eubanks, Lisa M; Choi, Jennifer L et al. (2015) Flagellin as carrier and adjuvant in cocaine vaccine development. Mol Pharm 12:653-62
Jiménez-Dalmaroni, Maximiliano J; Radcliffe, Catherine M; Harvey, David J et al. (2015) Soluble human TLR2 ectodomain binds diacylglycerol from microbial lipopeptides and glycolipids. Innate Immun 21:175-93
Lee, Ji Yeon; Kim, Hyoun Sook; Baek, In Wha et al. (2013) Overexpression, crystallization and preliminary X-ray crystallographic analysis of the variable lymphocyte receptor 2913 ectodomain fused with internalin B. Acta Crystallogr Sect F Struct Biol Cryst Commun 69:39-41
Penchala, Sravan C; Connelly, Stephen; Wang, Yu et al. (2013) AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A 110:9992-7
Grimster, Neil P; Connelly, Stephen; Baranczak, Aleksandra et al. (2013) Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate. J Am Chem Soc 135:5656-68
Hong, Minsun; Yoon, Sung-il; Wilson, Ian A (2012) Structure and functional characterization of the RNA-binding element of the NLRX1 innate immune modulator. Immunity 36:337-47
Bulawa, Christine E; Connelly, Stephen; Devit, Michael et al. (2012) Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A 109:9629-34

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