Review article
Autoreactive T cells in human type 1 diabetes

https://doi.org/10.1016/S0889-8529(03)00081-1Get rights and content

Section snippets

T-cell targets and epitopes

The considerable advances in autoimmune serology during 1975 to 1991 led to the unequivocal identification of three major islet autoantibody specificities, targeted against insulin, glutamic acid decarboxylase (GAD), and the islet tyrosine phosphatase, IA-2 [1], [2], [3]. Most T-cell epitope studies have focused on these three autoantigens—the existence of class-switched IgG autoantibodies strongly implies the influence of T-cell help—and this article discusses the evidence that T cells

Lessons from autoreactive CD4 T-cell clones in type 1 diabetes

Despite the reservations expressed previously, T-cell cloning remains one of the more enduring and successful approaches to epitope identification. Moreover, it offers the real possibility of ascertaining the epitopes targeted during disease development (although few cloning programs have used prediabetic subjects) and providing functional information regarding the responder T cells. On the negative side, cloning is laborious, frequently unsuccessful, and likely to be biased toward selection of

Lessons from autoreactive CD8 T-cell clones in type 1 diabetes

There is a considerable logic behind the need for studies on CD8 T-cell reactivity in T1D. CD8 T cells have potent cytotoxic potential and are the likely candidates for delivering the final toxic blow to β cells. In addition, they are well represented in the insulitic lesion and surrounded by abundant ligand in the form of class I MHC-expressing islet cells [38]. Moreover, recent evidence indicates that specific class I HLA molecules (HLA-A2.1 and HLA-A24) are associated with an increased risk

Antigen-specific regulatory T cells

Although most islet antigen-specific TCCs have been isolated from individuals with T1D, several studies have hinted at the presence of such T cells in individuals without the disease [33], [43], [44]. It is proposed that, in healthy individuals, these cells are held in check by several mechanisms, including the action of regulatory T cells, and that T1D arises in part because of a failure of these regulatory pathways. Against this background, several studies have pointed to a dysfunctional

Detection of autoreactive T cells ex vivo

The studies discussed previously highlight the importance of epitope discovery, which provides the ammunition for what is considered by many to be the real battle—that is, to enumerate and characterize islet autoreactive T cells directly ex vivo. Ideal assay characteristics include the ability to accurately quantify the frequency of antigen-specific T cells at a high level of sensitivity and specificity and the capacity to perform analysis of the quality of the response, through cytokine and

Summary

This systematic review of the information from studies on human autoreactive T cells is highly instructive. Studies on T-cell targets reveal the potential for disease-related and HLA allele-related peptide epitopes to be identified with current technology. The consistent lack of cloning success from nondiabetic control subjects, coupled with other studies on T-cell function [25], provides strong evidence that circulating autoreactive T cells are available for analysis in the peripheral blood of

First page preview

First page preview
Click to open first page preview

References (62)

  • K. Takahashi et al.

    Cytotoxic T cells to an epitope in the islet autoantigen IA-2 are not disease-specific

    Clin Immunol

    (2001)
  • B.O. Roep et al.

    Autoreactive T cell responses in insulin-dependent (type 1) diabetes mellitus. Report of the first International Workshop for Standardization of T Cell Assays

    J Autoimmun

    (1999)
  • M.A. Atkinson et al.

    Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes

    Lancet

    (1992)
  • L.W. Strijbosch et al.

    Limiting dilution assays. Experimental design and statistical analysis

    J Immunol Methods

    (1987)
  • D.A. Vignali

    Multiplexed particle-based flow cytometric assays

    J Immunol Methods

    (2000)
  • U. Andersson et al.

    Enumeration of IFN-gamma-producing cells by flow cytometry. Comparison with fluorescence microscopy

    J Immunol Methods

    (1988)
  • N.C. Schloot et al.

    Comparison of cytokine ELISpot assay formats for the detection of islet antigen autoreactive T cells. Report of the Third Immunology of Diabetes Society T-Cell Workshop

    J Autoimmun

    (2003)
  • J.P. Palmer et al.

    Insulin antibodies in insulin-dependent diabetics before insulin treatment

    Science

    (1983)
  • S. Baekkeskov et al.

    Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase

    Nature

    (1990)
  • M.A. Payton et al.

    Relationship of the 37,000- and 40,000-M(r) tryptic fragments of islet antigens in insulin-dependent diabetes to the protein tyrosine phosphatase-like molecule IA-2 (ICA512)

    J Clin Invest

    (1995)
  • A.C. Anderson et al.

    High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire

    J Exp Med

    (2000)
  • J. Diez et al.

    Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen

    Diabetes

    (2001)
  • M. Peakman et al.

    Characterization of preparations of GAD65, proinsulin, and the islet tyrosine phosphatase IA-2 for use in detection of autoreactive T-cells in type 1 diabetes: report of phase II of the Second International Immunology of Diabetes Society Workshop for Standardization of T-cell Assays in Type 1 Diabetes

    Diabetes

    (2001)
  • J.D. Altman et al.

    Phenotypic analysis of antigen-specific T lymphocytes

    Science

    (1996)
  • M. Peakman et al.

    Peptide immunotherapy: fighting fire with fire?

    Immunology

    (2001)
  • T.P. Cirrito et al.

    Deamidation of asparagine in a major histocompatibility complex-bound peptide affects T cell recognition but does not explain type B reactivity

    J Exp Med

    (2001)
  • B.O. Roep

    The role of T-cells in the pathogenesis of type 1 diabetes: from cause to cure

    Diabetologia

    (2003)
  • M. Peakman et al.

    Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4

    J Clin Invest

    (1999)
  • S.D. Patel et al.

    Identification of immunodominant T cell epitopes of human glutamic acid decarboxylase 65 by using HLA-DR(alpha10101, beta10401) transgenic mice

    Proc Natl Acad Sci U S A

    (1997)
  • M. Congia et al.

    T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin

    Proc Natl Acad Sci U S A

    (1998)
  • J. Liu et al.

    Major DQ8-restricted T-cell epitopes for human GAD65 mapped using human CD4, DQA10301, DQB10302 transgenic IA(null) NOD mice

    Diabetes

    (1999)
  • Cited by (0)

    Mark Peakman is a Diabetes UK Senior Clinical Research Fellow. Work from the authors' laboratory alluded to in this article was supported by Diabetes UK and The Wellcome Trust.

    View full text