T cells are integral to the study of type 1 diabetes (T1D) because CD4+ and CD8+ T cells are known to destroy beta cells.1 Discovery of reliable T-cell biomarkers in T1D research remains elusive. Replicable T-cell biomarkers would enable clinicians to predict disease progression and develop and monitor new therapies.1

The Current State of T-Cell Biomarkers

The 2 main classes of T-cell biomarkers in T1D include antigen specific, which encompasses markers picked up by assays that capture the number and function of the T cells specific to beta-cell autoantigens, and antigen agnostic, for which the assays measure T-cell properties without accounting for the specificity of T-cell receptors.1

The most promising candidates for T-cell biomarkers for T1D in the antigen-specific category, all of which have been replicated in 2 different laboratories, include1:

  • islet-specific CD8 T-cell frequency
  • islet-specific CD4 T-cell frequency and phenotype
  • inflammatory islet-specific T-cell signature

The leading antigen-agnostic biomarker candidates for T1D, most of which have been replicated in 2 different laboratories, include1:

  •  CD4 T-follicular helper cell frequency
  • CD4 regulatory T-cell transcript signature
  • CD4 effector T-cell resistance to suppression
  • forkhead box protein 3 (FOXP3)+ interferon-gamma (IFN-γ)+ regulatory T cells
  • CD4 T-cell interleukin-2 response
  • interleukin-17+ T-cell frequency

These biomarkers were tested for stage 3 T1D. Next steps for the biomarkers include standardization of the assays and clinical validation.1

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The T-cell biomarker candidates for treatment and response to T1D therapy in the antigen-specific category are1:

  • proinsulin CD8 T-cell frequency (for BHT-3021 plasmid-encoded proinsulin)
  • frequency of proinsulin-responsive T cells (for nasal insulin)
  • islet antigen CD8 T-cell frequency and phenotype (for teplizumab)
  • glutamic acid decarboxylase (GAD)65-responsive CD8 T cells (for GAD-alum)
  • islet-specific CD8 T-cell frequency and phenotype (for intradermal proinsulin peptide)

The antigen-agnostic T-cell biomarker counterparts for treatment and response include1:

  • CD4 central memory T-cell frequency (for abatacept)
  • CD8 T-cell exhaustion (for teplizumab)
  • CD3 and CD4 T-cell frequency (for rituximab)
  • CD4/CD8 T-cell ratio (for antithymocyte globulin plus G-CSF)
  • CD4 and CD8 naive T cells, effector T cells, and regulatory T cells (for alefacept)

Before these biomarkers can be used clinically, they need to be validated. To replicate the assays, researchers need to harmonize their testing methods in independent laboratories and validate their findings in statistically powered datasets. Once a biomarker clears these stages, regulatory authorities will determine its qualifications for use in clinical decision making.1

While prevention of T1D is not yet feasible, clinicians can characterize the extent of disease risk in patients.2 For example, the presence of islet autoantibodies can reliably predict whether a child will develop T1D; in children who have ≥2 islet autoantibodies, there is an approximate 85% risk for the development of clinical T1D within 15 years, and an almost 100% lifetime risk for T1D development.2