Abstract
T cell receptors (TCRs) are unique markers that define antigen specificity for a given T cell. With the evolution of sequencing and computational analysis technologies, TCRs are now prime candidates for the development of next-generation non-cell based T cell biomarkers, which provide a surrogate measure to assess the presence of antigen-specific T cells. Type 1 diabetes (T1D), the immune-mediated form of diabetes, is a prototypical organ specific autoimmune disease in which T cells play a pivotal role in targeting pancreatic insulin-producing beta cells. While the disease is now predictable by measuring autoantibodies in the peripheral blood directed to beta cell proteins, there is an urgent need to develop T cell markers that recapitulate T cell activity in the pancreas and can be a measure of disease activity. This review focuses on the potential and challenges of developing TCR biomarkers for T1D. We summarize current knowledge about TCR repertoires and clonotypes specific for T1D and discuss challenges that are unique for autoimmune diabetes. Ultimately, the integration of large TCR datasets produced from individuals with and without T1D along with computational ‘big data’ analysis will facilitate the development of TCRs as potentially powerful biomarkers in the development of T1D.
Highlights
A T cell receptor (TCR) determines antigen specificity of T cells by interacting with a peptide-major histocompatibility complex, and signals received through the T cell receptors (TCRs) along with the CD3 complex are the primary components that regulate function and fate of T cells
Individual T cells express unique TCRs, and TCR sequences can be used as an identifier of T cells that are specific to particular antigens and involved in immune responses
We will focus on the potential use of TCR sequences as non-cell based T cell biomarkers for type 1 diabetes (T1D), a tissue-specific autoimmune disease targeting insulin-secreting pancreatic beta cells [1,2,3]
Summary
A T cell receptor (TCR) determines antigen specificity of T cells by interacting with a peptide-major histocompatibility complex (peptide-MHC), and signals received through the TCR along with the CD3 complex are the primary components that regulate function and fate of T cells. Since a significant portion of disease-specific TCRs are likely to recognize islet antigens, TCR clonotypes expressed by islet antigen-specific T cells are reasonable candidates for TCR biomarkers Such T cell sources include peripheral blood T cells responding to islet antigen stimulation or enriched by staining with fluorescence-conjugated multimers consisting of an isletderived peptide and a particular HLA molecule [43,44,45]. Brusko and colleagues further corroborated this concept by studying a larger number of individuals using a generation sequencing technology that allows to analyze much higher numbers of T cells [72, 78] This high resolution analysis discovered that CD8 TCR clonotypes in the pancreas and draining lymph nodes are detected in peripheral blood more frequently than those expressed by CD4 T cells and provided important insights about the depth of TCR sequencing to achieve quantitative measurement. With rapidly evolving sequencing technologies, future efforts to identify islet epitope-
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