Identification of a CD8 T Cell That Can Independently Mediate Autoimmune Diabetes Development in the Complete Absence of CD4 T Cell Helper Functions

Abstract

Previous work has indicated that an important component for the initiation of autoimmune insulin-dependent diabetes mellitus (IDDM) in the NOD mouse model entails MHC class I-restricted CD8 T cell responses against pancreatic β cell Ags. However, unless previously activated in vitro, such CD8 T cells have previously been thought to require helper functions provided by MHC class II-restricted CD4 T cells to exert their full diabetogenic effects. In this study, we show that IDDM development is greatly accelerated in a stock of NOD mice expressing TCR transgenes derived from a MHC class I-restricted CD8 T cell clone (designated AI4) previously found to contribute to the earliest preclinical stages of pancreatic β cell destruction. Importantly, these TCR transgenic NOD mice (designated NOD.AI4αβ Tg) continued to develop IDDM at a greatly accelerated rate when residual CD4 helper T cells were eliminated by introduction of the scid mutation or a functionally inactivated CD4 allele. In a previously described stock of NOD mice expressing TCR transgenes derived from another MHC class I-restricted β cell autoreactive T cell clone, IDDM development was retarded by elimination of residual CD4 T cells. Hence, there is variability in the helper dependence of CD8 T cells contributing to the development of autoimmune IDDM. The AI4 clonotype represents the first CD8 T cell with a demonstrated ability to progress from a naive to functionally activated state and rapidly mediate autoimmune IDDM development in the complete absence of CD4 T cell helper functions.

The development and functions of CD4+ T cells expressing a transgenic TCR specific for an MHC-I-restricted tumor antigenic epitope

“…[1][2][3][4] However, exceptions have been reported in MHC-I-restricted alloantigen- 5 and autoantigen-specific 6,7 TCRtransgenic mice, in which there was no differentiation bias for CD8 1 T cells. In these transgenic mice, most of the CD4 1 T cells expressed an MHC-I-restricted transgenic TCR, which could be detected by specific anti-TCR antibodies, and an additional rearranged endogenous MHC-II-restricted TCR through which the CD4 1 T cells could be positively selected to maintain a normal ratio of CD4 1 to CD8 1 T cells.…”

“…By binding to MHC-I molecules on antigen-presenting cells, CD8 can strengthen MHC-I-restricted TCR signaling. 8,9 Although it was discovered by antibody staining in several MHC-I-restricted TCRtransgenic mice that the CD4 1 T cells expressed MHC-I-restricted transgenic TCRs, 5,6,7 so far, there has not been direct proof to determine whether the MHC-I-restricted transgenic TCRs on the CD4 1 T cells bind to the MHC-I/peptide complex.…”

Identification of naturally processed peptides bound to the class I MHC molecule H‐2Kd of normal and TAP‐deficient cells

“…Starting with the pioneering work of Rammensee and colleagues [5,9], Kd has been widely studied, and Kd-specific immune responses described in a number of experimental systems. These include CD8 T cell responses: (1) against viral and bacterial pathogens [6,[19][20][21][22]; (2) in the NOD mouse model of diabetic autoimmunity [23][24][25][26][27]; and, (3), to tumor antigens [28][29][30][31]. Despite these many studies, the number of identified endogenously processed peptides selected by Kd is small.…”

Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells Can Prevent Diabetes

“…A third islet-reactive, pathogenic NOD CTL, although initially thought to be specific to a dystrophia myotonica kinase, amino acids 138-146 (DMK [138][139][140][141][142][143][144][145][146] ) peptide, is actually reactive to insulin. [23][24][25] Interestingly, the relative distribution in the infiltrate of T cells varies considerably among individual mice, defining a unique immunological signature. [20][21][22][23] CD8 T cells reactive to glutamic acid decarboxylase (GAD65)-especially GAD65, amino acids 546-554 (GAD65 546-554 )-have also been identified in the NOD mouse.…”