Genetic and Therapeutic Control of Diabetogenic CD8 <sup>+</sup> T Cells
Bibliographic record
Abstract
CD8+ T cells are important contributors to the initiation and progression of type 1 diabetes (T1D). A very significant fraction of islet-associated CD8 T cells in NOD mice recognize epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), a non-essential endoplasmic reticulum-resident protein of unclear function. IGRP is also a target of CD8 T cell responses in human T1D patients. In NOD mice, most IGRP-reactive CD8 T cells target the IGRP(206-214) epitope and are diabetogenic. We have shown that the pathogenic activity of this T cell subset is controlled by genetic elements associated with diabetes susceptibility and resistance. One of these elements (Il2) has been recently implicated in susceptibility to several human autoimmune disorders, including TID. In mice, Il2 polymorphisms control a negative feedback mechanism initiated by activated, IL2-producing autoreactive T cells in the pancreatic lymph nodes that increases the regulatory activity of CD4+CD25+ T cells. Not all IGRP-reactive CD8 T cell clones are pathogenic, however, and we have evidence that some of these clonotypes are actually anti-diabetogenic. We had previously shown that administration of altered peptide ligands (APL) targeting IGRP(206-214)-reactive CD8 T cells resulted in diabetes protection only at doses that did not delete low-avidity clones, suggesting a protective role for these clonotypes. I discuss evidence showing that transgenic expression of a low-avidity IGRP(206-214)-reactive T cell receptor (TCR) efficiently prevents the development of insulitis and diabetes in NOD (non-obese diabetic) mice and that these cells do so by killing autoantigen-loaded antigen presenting cells in the pancreas-draining lymph nodes. These results illustrate a novel mechanism for regulation of immune responses to self-antigens and expose a new target for therapeutic intervention. Here I briefly summarize work done by us and others indicating that a prevalent subset of autoreactive CD8 T-cells in the NOD mouse are major (albeit likely dispensable) players in the pathogenesis of spontaneous autoimmune diabetes in the NOD mouse; that these T cells are targets of genetic elements affording autoimmune disease susceptibility and resistance; that they can either be diabetogenic or anti-diabetogenic according to their avidity for peptide/MHC; and that they can serve as useful targets for therapeutic intervention.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".