Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation
Maintaining and limiting T cell responses to constant antigen stimulation is critical to eliminate pathogens and maintain self-tolerance, respectively. Antigen recognition by the T cell receptor (TCR) induces signalling that can activate T cells to produce cytokines and downregulation of the TCR. Pr...
| Váldodahkkit: | , , , , |
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| Materiálatiipa: | Working paper |
| Almmustuhtton: |
2019
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| _version_ | 1826288116134051840 |
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| author | Trendel, N Kruger, P Nguyen, J Gaglione, S Dushek, O |
| author_facet | Trendel, N Kruger, P Nguyen, J Gaglione, S Dushek, O |
| author_sort | Trendel, N |
| collection | OXFORD |
| description | Maintaining and limiting T cell responses to constant antigen stimulation is critical to eliminate pathogens and maintain self-tolerance, respectively. Antigen recognition by the T cell receptor (TCR) induces signalling that can activate T cells to produce cytokines and downregulation of the TCR. Precisely how TCR downregulation controls T cell responses to constant antigen stimulation is controversial. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation but this relies on complete downregulation of the receptor or the ligand, which is not the case for the TCR. Here, we observed that primary human effector T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation. Perfect adaptation was observed across a wide variation in antigen concentration (2,000-fold) and affinity (100,000-fold) even with partial TCR downregulation. A mechanistic model showed that TCR downregulation produces imperfect adaptation, but when coupled to digital signalling led to perfect adaptation in cytokine production. A prediction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings highlight the role of even partial TCR downregulation in generating perfect adaptation with implications for costimulation and adoptive T cell therapies. |
| first_indexed | 2024-03-07T02:08:52Z |
| format | Working paper |
| id | oxford-uuid:9fe78434-cbf5-49bf-91e9-1529c9d7d3f4 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T02:08:52Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:9fe78434-cbf5-49bf-91e9-1529c9d7d3f42022-03-27T02:01:38ZPerfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulationWorking paperhttp://purl.org/coar/resource_type/c_8042uuid:9fe78434-cbf5-49bf-91e9-1529c9d7d3f4Symplectic Elements at Oxford2019Trendel, NKruger, PNguyen, JGaglione, SDushek, OMaintaining and limiting T cell responses to constant antigen stimulation is critical to eliminate pathogens and maintain self-tolerance, respectively. Antigen recognition by the T cell receptor (TCR) induces signalling that can activate T cells to produce cytokines and downregulation of the TCR. Precisely how TCR downregulation controls T cell responses to constant antigen stimulation is controversial. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation but this relies on complete downregulation of the receptor or the ligand, which is not the case for the TCR. Here, we observed that primary human effector T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation. Perfect adaptation was observed across a wide variation in antigen concentration (2,000-fold) and affinity (100,000-fold) even with partial TCR downregulation. A mechanistic model showed that TCR downregulation produces imperfect adaptation, but when coupled to digital signalling led to perfect adaptation in cytokine production. A prediction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings highlight the role of even partial TCR downregulation in generating perfect adaptation with implications for costimulation and adoptive T cell therapies. |
| spellingShingle | Trendel, N Kruger, P Nguyen, J Gaglione, S Dushek, O Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation |
| title | Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation |
| title_full | Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation |
| title_fullStr | Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation |
| title_full_unstemmed | Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation |
| title_short | Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation |
| title_sort | perfect adaptation of cd8 t cell responses to constant antigen input over a wide range of affinity is overcome by costimulation |
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