Abstract A053: Notch completes CD4 T cell help in CD8 T cells and ensures timely departure
Bibliographic record
Abstract
Abstract Efficient activation, expansion and differentiation of CD8 T cells depend on help from CD4+ T cells. Such help is especially critical for CD8 T cell responses against tumor antigens. Priming of CD8 T cells in lymph nodes (LN) involves two steps that are geographically and temporally separate. Naïve CD8 T cells are first preactivated by a migratory dendritic cell (DC) carrying antigen from tissues. Preactivated CD8 T cells must then find and interact with lymph node-resident XCR1+ DC that have been licensed for optimal CD8 T cell activation via CD4 T cell-mediated activation of CD40. The efferent signals provided by licensed CD8+XCR1+ DC to install the CD4 T cell help program in CD8 T cells are incompletely known. Moreover, it is not clear whether and, if so, how premature lymph node exit by preactivated CD8 T cells before receipt of help is avoided. Here, we show that completion of CD4 help delivery is coupled to the ability to leave lymph nodes through activation of Notch receptors on CD8 T cells. Expression of Notch receptors is induced on naïve CD8 T cells during the first step of priming, while CD40 ligation elicits expression of Notch ligands on XCR1+ lymph node resident DCs. Using a DNA vaccination model that allows induction of CD8 T cell responses in the presence or absence of CD4 T cell help, we show that the Notch1/2 receptors are necessary in CD8+ T cells for CD4+ T cell help-dependent proliferation and acquisition of effector capability. Correspondingly, RNA sequencing revealed that more than half of the genetic CD4 T cell help program in CD8 T cells depends on Notch. Strikingly, activated Notch1/2 deficient and unhelped CD8 T cells remain largely stuck in lymph nodes owing to a lack of expression of the lymph node exit receptor S1PR5. Control of expression of S1PR5 by Notch therefore ensures that preactivated CD8 T cells remain in lymph nodes until completion of their activation process by receiving the CD4 T cell help signal. Citation Format: Adrien Remi Gabriel Laurent, Julien Karrich, Nikolina Babala, Derk Amsen. Notch completes CD4 T cell help in CD8 T cells and ensures timely departure [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A053.
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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; both teacher heads agree on what is shown here.
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".