Mounting an antibody response is a major immune defense mechanism used by all vertebrates. Similarly, nearly all vaccinations work by inducing an antibody response. However, not all antibody responses are protective. Sometimes, the antibodies that are generated are either too few in number, or too low in affinity - these kinds of responses are ineffective. Paradoxically, a strong antibody response may not protect the host either. Often, an exuberant early antibody response is associated with a failure to produce antibodies that are more effective in clearing the infection later on and the establishment of persistent infections. This phenomenon has been observed in bacterial (e.g. Lyme disease), viral (e.g. Herpes) and parasitic (e.g. Toxoplasma gondii) infections. Thus, an antibody response that is either too weak or too strong is not protective and may even do more harm than good; only the response, which is just right, has the overall protective effect (the Goldilocks effect). The way to induce an antibody response has been well documented. However it is not at all clear how to regulate the strength of an antibody response in order to maximize protection. Because the lack understanding of the rules of augmenting antibody response, the rational design of effective vaccines remains unachievable and the prevention and treatment of chronic infections remain ineffective. This application, which is based on our recent findings suggesting T cells may be uniquely suited to modulate the strength of early B cell response, seeks to establish the basis to test this hypothesis. Our ultimate goal is to identiy the principles that regulate the magnitude of antibody response in hopes of uncovering new points of intervention that can be used in vaccine development as well as to treat chronic infections.

Public Health Relevance

Long lasting, high affinity, isotype-switched antibodies are vital for protection against many infectious diseases; the induction of antibodies like these is th underlying basis of most successful vaccines. In order to generate these antibodies, B cells require T cell help. While it is clear that one type of T cell, ?? T cells, are essential to this process, our recent results suggest another type of T cell, the ?? T cell, may play a crucial, thus far unappreciated role in generating this kind of antibody. This application seeks to expand upon these findings with a series of investigations that will test this hypothesis critically and focus n the possible mechanisms of ?? T cell help.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Kelly, Halonna R
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Stanford University
Schools of Medicine
United States
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Zeng, Xun; Meyer, Christina; Huang, Jun et al. (2014) Gamma delta T cells recognize haptens and mount a hapten-specific response. Elife 3:e03609