Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor alpha chain gene rearrangement - PubMed (original) (raw)

Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor alpha chain gene rearrangement

T P DiLorenzo et al. Proc Natl Acad Sci U S A. 1998.

Abstract

Nonobese diabetic (NOD) mice develop insulin-dependent diabetes mellitus due to autoimmune T lymphocyte-mediated destruction of pancreatic beta cells. Although both major histocompatibility complex class I-restricted CD8(+) and class II-restricted CD4(+) T cell subsets are required, the specific role each subset plays in the pathogenic process is still unclear. Here we show that class I-dependent T cells are required for all but the terminal stages of autoimmune diabetes development. To characterize the diabetogenic CD8(+) T cells responsible, we isolated and propagated in vitro CD8(+) T cells from the earliest insulitic lesions of NOD mice. They were cytotoxic to NOD islet cells, restricted to H-2Kd, and showed a diverse T cell receptor beta chain repertoire. In contrast, their alpha chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity-determining region 3 loop and a prevalence of Valpha17 family members frequently joined to the Jalpha42 gene segment. These results suggest that a number of the CD8(+) T cells participating in the initial phase of autoimmune beta cell destruction recognize a common structural component of Kd/peptide complexes on pancreatic beta cells, possibly a single peptide.

PubMed Disclaimer

Figures

Figure 1

Figure 1

MHC class I-restricted T cells are required for all but the terminal stages of diabetogenesis in NOD mice. Splenocytes from NOD donors of various ages were transferred to 4-week-old MHC class I-positive NOD-scid and MHC class I-negative NOD-scid.B2m null female recipients. The total number of recipients and those that became diabetic by 17 weeks post-transfer are plotted in A, and the mean time to disease onset post-transfer is plotted in B.

Similar articles

Cited by

References

    1. Atkinson M A, Maclaren N K. N Engl J Med. 1994;331:1428–1436. - PubMed
    1. Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y. Exp Anim. 1980;29:1–13. - PubMed
    1. Vyse T J, Todd J A. Cell. 1996;85:311–318. - PubMed
    1. Christianson S W, Shultz L D, Leiter E H. Diabetes. 1993;42:44–55. - PubMed
    1. Wang B, Gonzalez A, Benoist C, Mathis D. Eur J Immunol. 1996;26:1762–1769. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources