The antigen receptors on lymphocytes play pivotal roles in controlling the balance between tolerance and immunity. In B cells, the B cell antigen receptor (BCR) transmits signals that affect lymphocyte survival, proliferation, and differentiation. The BCR not only affects immune responses by transducing signals - it also internalizes antigen for presentation to the T cells. The relationship of BCR signaling and antigen internalization is controversial. Moreover, the molecular mechanisms by which co-receptors influence these processes are not known. The long-term objectives of the proposed research are to develop a suite of chemical tools to investigate B cell signaling, and to use information gained from them to control B cell signaling and the immune responses that result.
The Specific Aims follow.
The first aim i s to dissect the relationships between antigen signaling, internalization, and trafficking. New advances in polymer chemistry will be used to synthesize multivalent antigens that can illuminate antigen internalization and trafficking in live cells. Using latent fluorophores and modern imaging methods, we shall determine whether the processes of antigen signaling and internalization are linked or disconnected. In addition, studies in this aim will explore new approaches to deliver protein or peptide antigens to B cells for promoting immune responses.
The second aim i s to generate ligands that can bind to both the negative co-receptor CD22 and the BCR, and to investigate whether these ligands can influence signaling, and antigen internalization, and trafficking. We postulate that antigens that display oligosaccharides that bind CD22 can attenuate BCR signaling, and synthetic probes will be used to test this hypothesis. We anticipate that these studies could reveal an important role for glycosylation in regulating immune responses. In addition, the studies proposed in Aim 2 can yield new strategies to suppress activation of specific B cell populations, thereby promoting tolerance.
The third aim i s focused on using mass spectrometry to analyze how the synthetic antigens used in Aims 1 and 2 influence protein phosphorylation in B cells. The goal of this aim is to understand the molecular basis for the influence of the synthetic antigens on B cell signaling. We anticipate that the proposed investigations can give rise to new chemical biology strategies for eliciting immunity or tolerance.

Public Health Relevance

B cells are important components of the immune system because they can be activated by foreign (non-self) molecules to produce antibodies;however, B cells that become activated by self molecules (molecules within the organism) can give rise to autoimmune diseases. Compounds designed to result in B cell activation can promote immune responses (e.g., for vaccine development), and those that block B cell activation could lead to tolerance (e.g., for treating autoimmune diseases). The goal of this proposal is to synthesize new compounds that can be used to control B cell responses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (02))
Program Officer
Ferguson, Stacy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Earth Sciences/Natur
United States
Zip Code
Sheridan, Rachael T C; Hudon, Jonathan; Hank, Jacquelyn A et al. (2014) Rhamnose glycoconjugates for the recruitment of endogenous anti-carbohydrate antibodies to tumor cells. Chembiochem 15:1393-8
Courtney, Adam H; Bennett, Nitasha R; Zwick, Daniel B et al. (2014) Synthetic antigens reveal dynamics of BCR endocytosis during inhibitory signaling. ACS Chem Biol 9:202-10
Kiessling, Laura L; Grim, Joseph C (2013) Glycopolymer probes of signal transduction. Chem Soc Rev 42:4476-91
Li, Lingyin; Klim, Joseph R; Derda, Ratmir et al. (2011) Spatial control of cell fate using synthetic surfaces to potentiate TGF-beta signaling. Proc Natl Acad Sci U S A 108:11745-50
Kiessling, Laura L; Splain, Rebecca A (2010) Chemical approaches to glycobiology. Annu Rev Biochem 79:619-53
Derda, Ratmir; Musah, Samira; Orner, Brendan P et al. (2010) High-throughput discovery of synthetic surfaces that support proliferation of pluripotent cells. J Am Chem Soc 132:1289-95
Klim, Joseph R; Li, Lingyin; Wrighton, Paul J et al. (2010) A defined glycosaminoglycan-binding substratum for human pluripotent stem cells. Nat Methods 7:989-94
Courtney, Adam H; Puffer, Erik B; Pontrello, Jason K et al. (2009) Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation. Proc Natl Acad Sci U S A 106:2500-5
Mangold, Shane L; Carpenter, Rachael T; Kiessling, Laura L (2008) Synthesis of fluorogenic polymers for visualizing cellular internalization. Org Lett 10:2997-3000
Derda, Ratmir; Wherritt, Daniel J; Kiessling, Laura L (2007) Solid-phase synthesis of alkanethiols for the preparation of self-assembled monolayers. Langmuir 23:11164-7

Showing the most recent 10 out of 17 publications