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How many stages will T cell exhaustion go through?
How many stages will T cell exhaustion go through? Under continuous antigen exposure (such as tumors and chronic infections), T cells eventually fail to differentiate into the immune memory phenotype and are in a state of functional exhaustion, which is called T cell exhaustion.
Four stages of T cell exhaustion
T cell depletion is an important theory of tumor immunity at this stage. Therapies to reverse depletion, such as immune checkpoint inhibitors, are widely used in clinics. As an important means of immunotherapy, CAR-T therapy also needs to try to prevent cells from entering a state of exhaustion. Therefore, more and more in-depth studies have begun on T cell depletion.
Scientists from research units such as the University of Pennsylvania and Kanazawa University in Japan published an article in Immunity: Explaining the four-stage developmental framework of T cell exhaustion and the molecular characteristics of each stage.
According to Ly108 (a surrogate of TCF1) and CD69, depleted T cells are divided into four stages.
- Exhaustion progenitors 1 (T cell Exhaustion progenitors 1, Tex Prog1): Ly108+, resting state, local tissue
- T cell Exhaustion progenitors 2 (Tex Prog2): Ly108+, enters proliferation, has the ability to enter the blood
- T cell Exhaustion intermediate (TexInt): Tex Prog2 gradually loses TCF1, divides and transforms into the third stage-the intermediate Tex subgroup. At this time, depletion T regains some cytotoxic effect functions, especially in PD-L1 resistance. Increase after breaking.
- T cell Exhaustion terminally (Tex Term): Depleted T cells with high PD-1 expression finally enter the terminal stage, at which time they no longer respond to PD-L1/PD-1 blockade.
Gene transcription characteristics at different stages
The up-regulated genes in TexProg1 cells are involved in progenitor cell biology (Tcf7, Myb, Il7r, Sell), Tfh biology (Cxcr5, Icos) and positive costimulation (Cd28) (clusters 5 and 6). Texprog1 also contains interferon stimulation Genes (ISGs), including Irf7, OAs1 and Stat1 to enhance antiviral defense characteristics.
TexProg2 preferentially upregulated genes, enriched in genes related to cell cycle (cyclins and mki67) and cell movement (Anxa2, Itgb7, Alcam) (Cluster 1)
The transcription characteristics of TexInt cells include genes related to cytotoxic effects (such as Grzma, Grzmb, Prf1[cluster 4], Klrk1[cluster 4], Cx3cr1[cluster 8]) and TFs (Tbx21, Zeb2, Id2, Prdm1[cluster 4], With corresponding protein expression and gene ontology pathways. Natural killer (NK) cell-related biological characteristic genes (such as Klr family genes)
TexTerm upregulates inhibitory receptors (Pdcd1, Lag3, Tigit, Cd244 [cluster 2 and 7]) and molecules related to terminal depletion (Entpd1, Cd101, Cd38 [cluster 2 and 7]). Cluster 2 has a high degree of deviation for Texterm, including negative regulation of cell activation. Texterm cells also showed recent signs of TCR signaling, including high expression of Zap70, Nfatc1, and calcium influx pathway enrichment (cluster7). Although Tox is expressed by all Tex subgroups, Texterm has the highest expression.
- In this paper, we have conducted in-depth studies on the gene characteristics and transcriptional regulation of exhausted T cells at different developmental stages.
- This article is of great significance for immune checkpoint blocking therapy and companion diagnosis, and is suitable for downloading the original text for reading.
- Therefore, this article is only a brief description. Interested researchers can directly read the original text and download the document for in-depth study.
T cell exhaustion obviously plays an important role in tumor immunity, infection immunity, and autoimmunity. Penn’s work divided heterogeneous exhausted T cells into different stages of differentiation and development, and found that Tex Int T cells in the middle of exhaustion have the best response to immune checkpoint inhibitor therapy and can Restore the cytotoxic function of T cells. Therefore, companion diagnosis based on T cell depletion staging (or depleted T cell subtype) (such as the proportion of Tex Int) should play a positive role in better exerting the therapeutic effect of immune checkpoint inhibitors.
This article Cell Press is open for download. If you are interested, you can directly read the original link to enter the download interface.
Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms.
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