Kwok Laboratory
Back row: Junbao Yang, PhD; Michelle Roti, BA, Research Tech; Randi Nouv, lab aid; William W. Kwok, PhD, Principle Investigator; Venus Tan, BS, Research Tech; I-Ting Chow, PhD. Front row: Xinhui Ge, PhD; Eddie James, PhD, Laurie Huston, MS, Research Tech
The research focus of the Kwok laboratory is the study of antigen specific CD4+ T cells using tetramers. Historically, T cells with known antigen specificity have been difficult to detect and isolate. The use of class II tetramer reagents has provided a more effective approach for studying CD4+ T cell responses. Over the past decade, our research projects have used HLA class II tetramers to probe human CD4+ T cell responses in diverse disease settings.
Specific research emphases include:
1. Class II tetramer production: tetramer reagents for more than 25 different HLA class II alleles are produced through the Tetramer Core Laboratory. These reagents can be used to study human CD4+ T cell responses over a wide cross section of the population.
2. T cell epitope discovery: A robust, generalized approach has been developed and implemented to systematically identify CD4+ T cell epitopes. This approach can be applied to identify T cell epitopes within Categories A, B and C pathogens, tumor antigens, allergens and antigens associated with autoimmune diseases in human.
3. Autoimmune disease: Tetramers are used to examine autoreactive CD4+ T cells in diabetes, multiple sclerosis and scleroderma. We also are initiating studies using MHC-peptide array chips to examine autoreactive T cells.
4. Allergy: Tetramers are being applied to examine CD4+ T cell responses to environmental allergens. These studies should aid our understanding of the early stages of allergy development and suggest new strategies for therapy.
5. Emerging infectious pathogens: Tetramers present a novel approach to determine protective T cell epitopes within pathogens such as SARS, anthrax, and avian influenza. These studies can be initiated before a local epidemic occurs, aiding vaccine development and study of disease pathogenesis.
6. Molecular immune mechanisms: We are interested in the molecular mechanisms of HLA and autoimmune disease association that determine different disease outcomes. HLA that are linked to disease susceptibility or disease protection have been identified. Contrasting the behavior of susceptible and protective HLA alleles should provide insights into disease mechanisms and suggest strategies for intervention.
7. Adoptive immunotherapy: Our recent studies demonstrate that autoreactive T cells are present even in healthy subjects. Mechanisms must exist that regulate these autoreactive T cells. Our objectives include identifying and characterizing suppressive CD8+ T cells and antigen specific CD4+ Treg so these regulatory T cells can be amplified and used to halt the progression of autoimmunity.
Kwok Laboratory Publications
Roti M, Yang J, Berger D, Huston L, James EA, Kwok WW. Healthy Human Subjects Have CD4+ T Cells Directed against H5N1 Influenza Virus. J Immunol. 2008 180:1758-68.
Gebe JA, Kwok WW. Tracking antigen specific CD4+ T-cells with soluble MHC molecules. Methods Mol Med. 2007 136:39-50.
James EA, Bui J, Berger D, Huston L, Roti M, Kwok WW. Tetramer-guided epitope mapping reveals broad, individualized repertoires of tetanus toxin-specific CD4+ T cells and suggests HLA-based differences in epitope recognition. Int Immunol. 2007 19:1291-301.
James EA, Kwok WW. CD8+ suppressor-mediated regulation of human CD4+ T cell responses to glutamic acid decarboxylase 65. Eur J Immunol. 2007 37:78-86.
Yang J, James EA, Huston L, Danke NA, Liu AW, Kwok WW. Multiplex mapping of CD4 T cell epitopes using class II tetramers. Clin Immunol. 2006 120:21-32.
Yang J, Danke NA, Berger D, Reichstetter S, Reijonen H, Greenbaum C, Pihoker C, James EA, Kwok WW. Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects. J Immunol. 2006 176:2781-9.
Reichstetter S, Standifer NE, Geubtner KA, Liu AW, Agar SL, Kwok WW. Cytotoxic herpes simplex type 2-specific, DQ0602-restricted CD4 T+-cell clones show alloreactivity to DQ0601. Immunology. 2006 117:350-7.
Ettinger RA, Papadopoulos GK, Moustakas AK, Nepom GT, Kwok WW. Allelic variation in key peptide-binding pockets discriminates between closely related diabetes-protective and diabetes-susceptible HLA-DQB1*06 alleles. J Immunol. 2006 176:1988-98.
Danke NA, Yang J, Greenbaum C, Kwok WW. Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects. J Autoimmun. 2005 25:303-11.
Yang J, Huston L, Berger D, Danke NA, Liu AW, Disis ML, Kwok WW. Expression of HLA-DP0401 molecules for identification of DP0401 restricted antigen specific T cells. J Clin Immunol. 2005 25:428-36.
Danke NA, Koelle DM, Kwok WW. Persistence of herpes simplex virus type 2 VP16-specific CD4+ T cells. Hum Immunol. 2005 66:777-87.
Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004 172:5967-72.
Danke NA, Kwok WW. HLA class II-restricted CD4+ T cell responses directed against influenza viral antigens postinfluenza vaccination. J Immunol. 2003 71:3163-9.
Kwok WW. Challenges in staining T cells using HLA class II tetramers. Clin Immunol. 2003 06:23-8.
Kwok WW, Ptacek NA, Liu AW, Buckner JH. Use of class II tetramers for identification of CD4+ T cells. J Immunol Methods. 2002 268:71-81.
Gebe JA, Swanson E, Kwok WW. HLA class II peptide-binding and autoimmunity. Tissue Antigens. 2002 59:78-87.
Kwok WW, Gebe JA, Liu A, Agar S, Ptacek N, Hammer J, Koelle DM, Nepom GT. Rapid epitope identification from complex class-II-restricted T-cell antigens. Trends Immunol. 2001 22:583-8.
Novak EJ, Liu AW, Gebe JA, Falk BA, Nepom GT, Koelle DM, Kwok WW. Tetramer-guided epitope mapping: rapid identification and characterization of immunodominant CD4+ T cell epitopes from complex antigens. J Immunol. 2001 166:6665-70.
Kwok WW, Liu AW, Novak EJ, Gebe JA, Ettinger RA, Nepom GT, Reymond SN, Koelle DM. HLA-DQ tetramers identify epitope-specific T cells in peripheral blood of herpes simplex virus type 2-infected individuals: direct detection of immunodominant antigen-responsive cells. J Immunol. 2000 164:4244-9.
Novak EJ, Liu AW, Nepom GT, Kwok WW. MHC class II tetramers identify peptide-specific human CD4(+) T cells proliferating in response to influenza A antigen. J Clin Invest. 1999 104:R63-7.
Kwok WW, Domeier ME, Johnson ML, Nepom GT, Koelle DM. HLA-DQB1 codon 57 is critical for peptide binding and recognition. J Exp Med. 1996 183:1253-8.