Dr. Buckner’s laboratory focuses on identifying the underlying mechanisms by which the adaptive immune response to self-antigens becomes pathogenic in the setting of human autoimmune disease. To this end, Dr. Buckner’s group studies how both regulatory and effector mechanisms are altered in autoimmunity. The Buckner group studies the following autoimmune diseases: type 1 diabetes (T1D), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus, and relapsing polychondritis. They have extensive experience in MHC class II tetramers, T cell cloning, T and B cell functional assays and phenotyping of human lymphocytes.
Genetic variants associated with autoimmune disease
Dr. Buckner’s group has a long-standing interest in determining the functional impact of genetic variants associated with T1D and lupus including PTPN22, IL2RA, PTPN2, BANK1, IFIH1 and TYK2. Their work has shown that the PTPN22 risk variant alters B cell signaling and B cell development, and their studies of both the IL2RA and the PTPN2 risk variants associated with T1D have demonstrated an association with reduced responsiveness to IL-2 signaling in regulatory T cells in T1D and MS. Ongoing phenotype-genotype studies are determining the functional impact of additional risk variants, alone and in combination, on specific programs implicated in autoimmune disease. The approach in collaboration with Dr. David Rawlings, Seattle Children’s Research Institute, integrates studies of primary human cells from healthy controls and individuals with autoimmune disease, novel model systems and innovative gene editing technologies.
Cytokine signaling pathways
The Buckner group’s work on IL-2 signaling highlights the importance of this pathway in the maintenance of FOXP3 expression in regulatory T cells in T1D. Furthermore, recent work from the Buckner lab has shown that the T cell response to IL-6 signaling is enhanced in T1D and relapsing-remitting multiple sclerosis. Ongoing studies are investigating how alterations in response to cytokine signaling influence the expansion and persistence of pathogenic autoreactive effector T cells. These studies examine the response to cytokine signaling in the context of clinical, genetic and immunologic heterogeneity of human subjects, which is critical for the development of precision medicine for the prevention and treatment of autoimmune disease.
Antigen-specific T cells in rheumatoid arthritis
These studies are characterizing antigen-specific T cells in RA using tools that include multiplex tetramer approaches. The long-term goal of these studies is to understand the specificity of the pathogenic response in RA, and to determine how the frequency and phenotype of antigen-specific T cells is altered with respect to disease activity and response to therapy. Recent work from the Buckner lab has shown that citrulline-specific Th1 cells are increased in RA and that the frequency of these cells is influenced by disease duration and therapy. The Buckner group is also assessing antigen-specific T cell responses with respect to T cell repertoire and transcriptional profile in both individuals with RA and in individuals at high risk for developing RA.
Development of regulatory T cell-based therapy
The long-term goal of these studies is to develop therapies that enhance the ability of regulatory T cells to suppress the autoimmune response in both T1D and RA. Recent work has focused on in vitro induction, isolation and expansion of human tissue-specific regulatory T cells. Ongoing studies, in collaboration with Dr. David Rawlings and Dr. Andrew Scharenberg at Seattle Children’s Research Institute, are using novel gene editing tools to engineer FOXP3-stabilized, tissue-specific T cells.