The class II major histocompatibility complex (MHCll) pathway for antigen processing, presentation and T cell activation is believed to be limited to protein antigens. As a result all known vaccines utilize proteins to generate long-term immune protection. However, published work has now identified zwitterionic capsular polysaccharides (ZPSs) from encapsulated bacteria like Staphylococcus aureus as a new class of MHCII-dependent ? T-cell antigens. Recent data further demonstrates that ZPS antigens are processed to small fragments in antigen presenting cells through oxidation and then associate with MHCII proteins. To begin defining the key steps in this newly expanded MHCII paradigm, two specific aims have been designed. (1) Analysis of oxidation-mediated polysaccharide antigen processing: exploration of the role(s) of oxidant production in ZPS processing during host responses to encapsulated bacteria. (2) Characterization of the MHCII binding site for polysaccharide T cell-dependent antigens: identification of key contacts on MHCII proteins during ZPS antigen binding. The manner in which ZPS antigens are processed by oxidants together with the contacts made during MHCII binding represent new frontiers in the study of adaptive immune responses and vaccine design against encapsulated bacteria. These results may even provide the biochemical basis for the enhancement of T cell responses against other carbohydrates. The K22 award would facilitate my immediate goal of obtaining a tenure-track academic appointment by giving me significant momentum and marketability in the competitive interview process. More importantly, it would help me to develop my early career as an independent scientist working to apply traditional biochemistry and biophysics to immunological questions, with particular long-term interests in rational therapeutic design. From this point of view, the proposed studies represent the culmination of my educational goals as a biochemistry graduate student and a fellow studying immunology and pathogenesis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI062707-02
Application #
7189068
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2006-03-01
Project End
2008-02-29
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$107,991
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Lewis, Colleen J; Cobb, Brian A (2011) Adaptive immune defects against glycoantigens in chronic granulomatous disease via dysregulated nitric oxide production. Eur J Immunol 41:2562-72
Kreisman, Lori S C; Cobb, Brian A (2011) Glycoantigens induce human peripheral Tr1 cell differentiation with gut-homing specialization. J Biol Chem 286:8810-8
Lewis, Colleen J; Cobb, Brian A (2010) Carbohydrate oxidation acidifies endosomes, regulating antigen processing and TLR9 signaling. J Immunol 184:3789-800
Brokaw, Ann; Cobb, Brian A (2009) A Simple Test Tube-Based ELISA Experiment for the High-School Classroom. Biochem Mol Biol Educ 37:243-248
Velez, Christopher D; Lewis, Colleen J; Kasper, Dennis L et al. (2009) Type I Streptococcus pneumoniae carbohydrate utilizes a nitric oxide and MHC II-dependent pathway for antigen presentation. Immunology 127:73-82
Clark, Nivedita M; Marinis, Jill M; Cobb, Brian A et al. (2008) MEKK4 sequesters RIP2 to dictate NOD2 signal specificity. Curr Biol 18:1402-8
Cobb, Brian A; Kasper, Dennis L (2008) Characteristics of carbohydrate antigen binding to the presentation protein HLA-DR. Glycobiology 18:707-18
Kreisman, Lori S C; Friedman, Julia H; Neaga, Andreea et al. (2007) Structure and function relations with a T-cell-activating polysaccharide antigen using circular dichroism. Glycobiology 17:46-55