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. New technologies, such as single cell RNAseq and time of flight mass cytometry (CyTOF), are now being used in parallel with Class II tetramers and other antigen specific T cell assays to provide a high dimensional data analysis of antigen specific T cells.
From left to right: Luis Pow Sang, Diego Archila, Cynthia Cousens-Jacobs, I-Ting Chow, Bill Kwok, Cosette LeCiel, Xiaomin Wen, Quinn DeGottardi, Nadia Torres-Chen, Ying Ying kong, Richard Notturno
Specific Areas of Research
Class II tetramer production
Tetramer reagents for more than 30 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. Class II tetramers that can be used for CYTOF mass cytometry are also being produced in the core laboratory.
T cell epitope discovery
A robust, generalized approach has been developed and implemented to systematically identify CD4+ T cell epitopes. This approach is applied to identify T cell epitopes within Categories A, B and C pathogens, tumor antigens, allergens and antigens associated with autoimmune diseases in humans.
Tetramers are used to examine autoreactive CD4+ T cells in type 1 diabetes, multiple sclerosis and systemic lupus erythematosus. Experiments are designed to determine the molecular mechanisms of HLA and autoimmune disease association. HLA that are linked to disease susceptibility or disease protection have been identified. Contrasting the behavior of T cells restricted by susceptible and protective HLA alleles should provide insights into disease mechanisms and suggest strategies for intervention.
Tetramers are being applied to examine CD4+ T cell responses to environmental allergens such as dust mites, cat dander, pollens and food allergens such as peanut, tree nuts, milk and egg in non-allergic and allergic subjects. Allergen specific T cell responses are also being monitored during the course of immunotherapy. These studies should aid our understanding of the early stages of allergy development and suggest new strategies for therapy. New technology platforms, such as CyTOF and Fluidigm C1, are being used in some of these studies.
Tetramers present a novel approach to study T cell responses against pathogens such as seasonal and avian influenza, human rhinovirus, Japanese Encephalitis virus and Yellow Fever virus. Research participants that are exposed to these organisms by either infection or vaccination are recruited. Studies are carried out to characterize antigen specific T cell responses and to dissect the underlying mechanism for the development of long lasting protective immune responses.
Antigen specific immune responses
Other techniques are also being utilized to examine the collaboration between antigen specific T cell and B cell responses.