We will carry out deep sequencing of rearranged immunoglobulin (Ig) and T cell receptor (TCR) genes from lymphocytes in human subjects responding to several distinct viral (H1N1 influenza, varicella zoster, and measles/mumps/rubella) and bacterial (meningococcal) vaccines, as well as natural infections with HI N1 influenza and varicella zoster. Our initial analysis will examine rearranged Ig and TCR repertoire in total peripheral blood lymphocyte populations. Subsequent analysis will define repertoire in subsets of B cells and T-cells selected on the basis of their immunophenotype or antigen binding activity. These data will provide a fine-detailed view of the number, size, and receptor sequence features of expanded B and T cell clones arising during these human immune responses, and will be correlated with a variety of parallel serological and cellular functional immune assays from the Stanford Human Immune Monitoring Research (SHIMR) Center to enable detection ofthe characteristics of effective vaccination and the immune response to natural infection. The effects of patient age and genetic background on immune responses will also be assessed in a subset of experiments. Our intertwined goals for the five-year period of this grant are: 1. Characterize immune receptor populations in adults before and following immunization with influenza H1N1 vaccine and following natural infection by H1N1. 2. Characterize immune receptor populations in adults before and following immunization with a conjugated bacterial polysaccharide vaccine (Menactra). 3. Characterize immune receptor populations following vaccination against Varicella Zoster (in older adults) and measles virus (in children). 4. Develop new quantitative analytical tools for high throughput immunome data and use these tools to characterize the clinical relevance of commonalities and differences in immune spectra amongst immunized individuals. 5. Interface immune repertoire data with additional immunophenotyping data including HLA type, antibody binding affinity and specificity, target killing, cytokine production, signaling response spectra, and cellular surface marker distribution.
We will apply new DNA sequencing methods to study the unique receptors expressed by populations of B and T cells in the immune system following protective vaccination against viral and bacterial diseases, and during active infections. Better understanding of which B cells and T cells respond to vaccination and infection, and which are most helpful for fighting disease, will aid the design and testing of new vaccines.
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|Qi, Qian; Zhang, David W; Weyand, Cornelia M et al. (2014) Mechanisms shaping the naïve T cell repertoire in the elderly - thymic involution or peripheral homeostatic proliferation? Exp Gerontol 54:71-4|
|Shekhar, Karthik; Brodin, Petter; Davis, Mark M et al. (2014) Automatic Classification of Cellular Expression by Nonlinear Stochastic Embedding (ACCENSE). Proc Natl Acad Sci U S A 111:202-7|
|Jackson, Katherine J L; Liu, Yi; Roskin, Krishna M et al. (2014) Human responses to influenza vaccination show seroconversion signatures and convergent antibody rearrangements. Cell Host Microbe 16:105-14|
|Lu, Yuan; Welsh, John P; Swartz, James R (2014) Production and stabilization of the trimeric influenza hemagglutinin stem domain for potentially broadly protective influenza vaccines. Proc Natl Acad Sci U S A 111:125-30|
|Wang, Chen; Liu, Yi; Xu, Lan T et al. (2014) Effects of aging, cytomegalovirus infection, and EBV infection on human B cell repertoires. J Immunol 192:603-11|
|O'Gorman, William E; Huang, Huang; Wei, Yu-Ling et al. (2014) The Split Virus Influenza Vaccine rapidly activates immune cells through Fc? receptors. Vaccine 32:5989-97|
|Rosenberg-Hasson, Yael; Hansmann, Leo; Liedtke, Michaela et al. (2014) Effects of serum and plasma matrices on multiplex immunoassays. Immunol Res 58:224-33|
|Kay, Alexander W; Fukuyama, Julia; Aziz, Natali et al. (2014) Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy. Proc Natl Acad Sci U S A 111:14506-11|
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