Using the T Cell Receptor as a Biomarker in Type 1 Diabetes

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.

Immunological balance between Treg and Th17 lymphocytes as a key element of type 1 diabetes progression in children

“…State-ofthe-art data also indicate the potential role of selected receptors on T lymphocytes that are specific for T1D. These results mention the possibility of developing a biomarker considering cellular parameters and disease activity, particularly on the clonotypes of lymphocytes circulating from the pancreatic tissue into the bloodstream (8). Although numerous factors are considered today as essential in the pathogenesis of T1D, increasing attention is paid to the immunological pathways' involvement in the endocrine disruption.…”

Eras of designer Tregs: Harnessing synthetic biology for immune suppression

“…HLA restriction is a major limitation to the wider application of TCR Tregs in non‐HLA‐associated diseases as high diversity in HLA haplotype limits the pool of patients that can be treated with a single TCR construct. Secondly, the TCR landscape of islet‐infiltrating T cells is extensively characterized, 71 providing a large pool of TCRs that are highly reactive to islet‐associated antigens and are common across a number of patients. These tools and knowledge have contributed to the development of multiple human TCR Tregs which are restricted by HLA‐DR3, HLA‐DR4, or HLA‐DQ8 and recognize beta‐cell‐derived peptides, such as islet antigen 2, glutamate decarboxylase 65, islet‐specific glycose‐6‐phosphatase catalytic subunit‐related protein, and preproinsulin 69,72–75 .…”

Induction of antigenic immune tolerance to delay type 1 diabetes – challenges for clinical translation

“…However, defining these features would necessitate reliable tracking of smaller subsets of autoreactive cells in blood in a clinical setting, which is not easily done. Indeed, the frequency of such subsets in peripheral blood, is very low, that is, approximately 1 per 10 5 to 1 per 10 6 cells [36], as they are naturally sequestered in the targeted organ and draining lymph nodes. Thus, their detection either is subject to profound variability or will require secondary expansion in vitro , possibly altering their functional phenotype artificially (Fig.…”

“…In the pursuit of the ideal biomarker(s), novel technologies, the maturity of which is steadily increasing, offer hope. For example, single-cell RNA sequencing [37,38] and profiling of T-cell receptors [36,58,59] used alone or in combination appear promising but, alas, unvalidated as prognostic, diagnostic, or mechanistic proxies of T1D risk, onset, or progression. In alignment with the central role of T cells in T1D immunopathogenesis, recent studies have found distinct T-cell repertoire profiles [60,61].…”