Internal regulation between constitutively expressed T cell coinhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants
Bibliographic record
Abstract
Abstract Several coinhibitory receptors are upregulated upon activation, whereas a small number of coinhibitory receptors are expressed constitutively by naive T cells. The relationship between constitutively expressed coinhibitors is unknown. We found an inverse relationship between two constitutively expressed coinhibitors, CD5 and BTLA; BTLA expression was low in the thymus and high in the periphery, corresponding respectively with high and low CD5 expression. Germline or induced deletion of Btla in somatic cells demonstrated a causal relationship between BTLA expression and CD5 levels in T cells of central and peripheral lymphoid tissues. The effect of BTLA on CD5 expression on thymic and peripheral CD4 T cells was due to BTLA signaling, rather than signaling by its ligand, the herpes virus mediator (HVEM). Regulation was maintained in mice with a non-signaling HVEM mutant but was lost in Tnfrsf14 −/− ( Hvem −/− ) mice. Increased CD5 levels have been positively associated with increased recognition of self-peptide MHC complexes. Thus, control of CD5 expression by BTLA signals early in T cell ontogeny suggested that BTLA might be important for establishing self-tolerance in newly generated T cells. Consistent with this concept, we found that BTLA, as well as the inducible coinhibitor PD-1, were needed post thymic selection in recent thymic emigrants (RTE) to establish self-tolerance. RTE lacking BTLA caused a multiorgan autoimmune disease whose development required CD4 T cells and MHC class II. Together, our findings identify a negative regulatory pathway allowing constitutively expressed coinhibitory receptors to calibrate their expression in thymic T cell differentiation. Expression of constitutive and induced coinhibitory receptors is needed to establish tolerance in the periphery for RTE.
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".