Perfect adaptation of CD8(+) T cell responses to constant antigen input over a wide range of affinities is overcome by costimulation
Maintaining and limiting T cell responses to constant stimulation with antigen are critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) activates signaling that stimulates T cells to produce cytokines and also leads to the down-regul...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Association for the Advancement of Science
2021
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| _version_ | 1826256805408276480 |
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| author | Trendel, N Kruger, P Gaglione, S Nguyen, J Pettmann, J Sontag, ED Dushek, O |
| author_facet | Trendel, N Kruger, P Gaglione, S Nguyen, J Pettmann, J Sontag, ED Dushek, O |
| author_sort | Trendel, N |
| collection | OXFORD |
| description | Maintaining and limiting T cell responses to constant stimulation with antigen are critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) activates signaling that stimulates T cells to produce cytokines and also leads to the down-regulation of cell surface TCRs. In other systems, receptor down-regulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation, which requires complete down-regulation of the receptor or the ligand; however, this is not the case for the TCR. Here, we observed that in vitro–expanded primary human T cells exhibited perfect adaptation with respect to cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR down-regulation. By directly fitting a mechanistic model to these data, we showed that TCR down-regulation produced imperfect adaptation, but, when coupled to a switch, produced perfect adaptation in terms of cytokine production. A prediction of this model was that TCR signaling induced by peptide-bound major histocompatibility complex (pMHC) continues after adaptation, which we confirmed by showing that, whereas costimulation could not prevent adaptation, signaling by the costimulatory receptors CD28 and 4-1BB reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We showed that adaptation also applied to first-generation chimeric antigen receptor (CAR) T cells but was partially avoided with second-generation CARs. These findings highlight that perfect adaptation limits the responses of T cells, rendering them dependent on costimulation for sustained responses.
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| first_indexed | 2024-03-06T18:08:06Z |
| format | Journal article |
| id | oxford-uuid:021db7d3-94b5-497c-88c3-3473d66e779c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:08:06Z |
| publishDate | 2021 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | oxford-uuid:021db7d3-94b5-497c-88c3-3473d66e779c2022-03-26T08:38:42ZPerfect adaptation of CD8(+) T cell responses to constant antigen input over a wide range of affinities is overcome by costimulationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:021db7d3-94b5-497c-88c3-3473d66e779cEnglishSymplectic ElementsAmerican Association for the Advancement of Science2021Trendel, NKruger, PGaglione, SNguyen, JPettmann, JSontag, EDDushek, OMaintaining and limiting T cell responses to constant stimulation with antigen are critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) activates signaling that stimulates T cells to produce cytokines and also leads to the down-regulation of cell surface TCRs. In other systems, receptor down-regulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation, which requires complete down-regulation of the receptor or the ligand; however, this is not the case for the TCR. Here, we observed that in vitro–expanded primary human T cells exhibited perfect adaptation with respect to cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR down-regulation. By directly fitting a mechanistic model to these data, we showed that TCR down-regulation produced imperfect adaptation, but, when coupled to a switch, produced perfect adaptation in terms of cytokine production. A prediction of this model was that TCR signaling induced by peptide-bound major histocompatibility complex (pMHC) continues after adaptation, which we confirmed by showing that, whereas costimulation could not prevent adaptation, signaling by the costimulatory receptors CD28 and 4-1BB reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We showed that adaptation also applied to first-generation chimeric antigen receptor (CAR) T cells but was partially avoided with second-generation CARs. These findings highlight that perfect adaptation limits the responses of T cells, rendering them dependent on costimulation for sustained responses. |
| spellingShingle | Trendel, N Kruger, P Gaglione, S Nguyen, J Pettmann, J Sontag, ED Dushek, O Perfect adaptation of CD8(+) T cell responses to constant antigen input over a wide range of affinities is overcome by costimulation |
| title | Perfect adaptation of CD8(+) T cell responses to constant antigen input over a wide range of affinities is overcome by costimulation |
| title_full | Perfect adaptation of CD8(+) T cell responses to constant antigen input over a wide range of affinities is overcome by costimulation |
| title_fullStr | Perfect adaptation of CD8(+) T cell responses to constant antigen input over a wide range of affinities is overcome by costimulation |
| title_full_unstemmed | Perfect adaptation of CD8(+) T cell responses to constant antigen input over a wide range of affinities is overcome by costimulation |
| title_short | Perfect adaptation of CD8(+) T cell responses to constant antigen input over a wide range of affinities is overcome by costimulation |
| title_sort | perfect adaptation of cd8 t cell responses to constant antigen input over a wide range of affinities is overcome by costimulation |
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