Discriminative T Cell Recognition of Cross-Reactive Islet-Antigens Is Associated with HLA-DQ8 Transdimer–Mediated Autoimmune Diabetes
This week we profile a recent publication in Science Advances from Dr. I-Ting Chow (pictured, left)
in the laboratory of Dr. William Kwok (right) at Benaroya Research Institute at Virginia Mason.
Can you provide a brief overview of your lab’s current research focus?
Our lab focuses on the characterization of disease-relevant CD4 T lymphocytes in various human disease settings. CD4 T lymphocytes are important mediators for the immune system and recognize peptide antigens in complex with the human leukocyte antigen class II (HLAII) molecules. With the state-of-the-art HLAII tetramer platform developed by the Tetramer Lab Core at Benaroya Research Institute, we identify antigenic peptides (epitopes) as well as the contribution of cognate CD4 T lymphocyte in the progression and protection of diseases.
What is the significance of the findings in this publication?
HLAIIs are a prominent risk factor for several autoimmune diseases, including multiple sclerosis (MS), autoimmune diabetes (type 1 diabetes or T1D), and rheumatoid arthritis (RA). T1D is predominantly linked to genetically predisposed individuals carrying HLA-DQ8 or HLA-DQ2. HLA-DQ8/DQ2 heterozygous individuals confer a synergistically higher risk for disease. Epidemiological studies link this extremely high-risk to the naturally occurring trans-complementary molecule HLA-DQ8 transdimer. This publication made a key discovery about the structural and functional characteristics of T cells that cross-recognize HLA-DQ8 and HLA-DQ8 transdimer in complex with epitopes derived from important islet antigens. It also uncovered a molecular and functional paradigm whereby disease risk may be altered primarily by increased T cell promiscuity driven by disease-predisposing HLAIIs. The reported mechanism is distinct from selective presentation of autoimmune peptides or altered T cell repertoires by HLAIIs as the primary drivers of autoimmune pathology.
What are the next steps for this research?
The findings could lead to new approaches to prevent or stop the progression of T1D. The common architecture of T-cell recognition between T1D-predisposing HLAIIs may be important for the immunomodulation of T1D. Areas of future research could include modulation of T-cell/HLA-peptide affinities by gene editing/nanoparticle-based immunotherapy for more effective induction of anergy/apoptosis or conversion of naïve low-avidity autoreactive T cells into memory-like autoregulatory cells. In addition, CD4 T lymphocytes that recognize immunodominant and disease-relevant epitopes identified in this publication could be potential prognostic and predictive biomarkers for T1D.
This work was funded by:
This work was supported by DP3 DK097653 and DK106909 grants from the National Institutes of Health.