Enhanced PI3K/Akt-mediated survival of memory Th1 cells in type-1 diabetics and healthy controls carrying the autoimmunity-associated 1858T allelic variant of PTPN22 (P4097)
Bibliographic record
Abstract
Abstract A C-to-T polymorphism (1858T) in the PTPN22 gene alters the function of the lymphoid phosphatase Lyp and confers increased risk for autoimmunity. The PTPN22 1858T allele is associated with altered TCR signaling and expanded memory T cell pool. To determine its impact on lineage commitment and survival, naïve CD4+ T cells from healthy subjects carrying risk or non-risk alleles were differentiated in vitro. Cultures of T cells bearing PTPN22 1858T displayed similar proliferative capacity but reduced activation-induced cell death, yielding more IFNγ+ Th1 cells than non-risk controls. In vivo, PTPN22 1858T subjects mounted enhanced IFNγ responses to the pneumococcal vaccine Prevnar, but not IL-2 production or T cell proliferation. Examination of TCR-mediated signaling revealed that elevated pAkt activity and BCL2 expression were associated with the PTPN22 1858T allele and correlated with enhanced T cell survival during in vitro stimulation. This phenotype was mirrored in T cell cultures from type-1 diabetic subjects, regardless of their PTPN22 genotype, and was reversed by a PI3Kδ-specific inhibitor. Our studies indicate that the autoimmunity-associated PTPN22 1858T allele protects T cells from apoptosis via elevated PI3K/Akt signaling, leading to the accumulation of pro-inflammatory memory Th1 cells. This T-cell intrinsic defect is a general feature of T1D and inhibition of PI3Kδ offers a potential avenue for pharmacological intervention.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".