CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens.
Adaptation of the T cell activation threshold may be one mechanism to control autoreactivity. To investigate its occurrence in vivo, we engineered a transgenic mouse model with increased TCR-dependent excitability by expressing a Zap70 gain-of-function mutant (ZAP-YEEI) in postselection CD8 thymocyt...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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2005
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| _version_ | 1797099779019243520 |
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| author | Marquez, M Ellmeier, W Sanchez-Guajardo, V Freitas, A Acuto, O Di Bartolo, V |
| author_facet | Marquez, M Ellmeier, W Sanchez-Guajardo, V Freitas, A Acuto, O Di Bartolo, V |
| author_sort | Marquez, M |
| collection | OXFORD |
| description | Adaptation of the T cell activation threshold may be one mechanism to control autoreactivity. To investigate its occurrence in vivo, we engineered a transgenic mouse model with increased TCR-dependent excitability by expressing a Zap70 gain-of-function mutant (ZAP-YEEI) in postselection CD8 thymocytes and T cells. Increased basal phosphorylation of the Zap70 substrate linker for activation of T cells was detected in ZAP-YEEI-bearing CD8 T cells. However, these cells were not activated, but had reduced levels of TCR and CD5. Moreover, they produced lower cytokine amounts and showed faster dephosphorylation of linker for activation of T cells and ERK upon activation. Normal TCR levels and cytokine production were restored by culturing cells in the absence of TCR/spMHC interaction, demonstrating dynamic tuning of peripheral T cell responses. The effect of avidity for self-ligand(s) on this sensory adaptation was studied by expressing ZAP-YEEI in P14 or HY TCR transgenic backgrounds. Unexpectedly, double-transgenic animals expressed ZAP-YEEI prematurely in double-positive thymocytes, but no overt alteration of selection processes was observed. Instead, modifications of TCR and CD5 expression due to ZAP-YEEI suggested that signal tuning occurred during thymic maturation. Importantly, although P14 x ZAP-YEEI peripheral CD8 T cells were reduced in number and showed lower Ag-induced cytokine production and limited lymphopenia-driven proliferation, the peripheral survival/expansion and Ag responsiveness of HY x ZAP-YEEI cells were enhanced. Our data provide support for central and peripheral sensory T cell adaptation induced as a function of TCR avidity for self-ligands and signaling level. This may contribute to buffer excessive autoreactivity while optimizing TCR repertoire usage. |
| first_indexed | 2024-03-07T05:28:28Z |
| format | Journal article |
| id | oxford-uuid:e15da84d-fa63-49c2-9a56-a08fd5549054 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:28:28Z |
| publishDate | 2005 |
| record_format | dspace |
| spelling | oxford-uuid:e15da84d-fa63-49c2-9a56-a08fd55490542022-03-27T09:53:58ZCD8 T cell sensory adaptation dependent on TCR avidity for self-antigens.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e15da84d-fa63-49c2-9a56-a08fd5549054EnglishSymplectic Elements at Oxford2005Marquez, MEllmeier, WSanchez-Guajardo, VFreitas, AAcuto, ODi Bartolo, VAdaptation of the T cell activation threshold may be one mechanism to control autoreactivity. To investigate its occurrence in vivo, we engineered a transgenic mouse model with increased TCR-dependent excitability by expressing a Zap70 gain-of-function mutant (ZAP-YEEI) in postselection CD8 thymocytes and T cells. Increased basal phosphorylation of the Zap70 substrate linker for activation of T cells was detected in ZAP-YEEI-bearing CD8 T cells. However, these cells were not activated, but had reduced levels of TCR and CD5. Moreover, they produced lower cytokine amounts and showed faster dephosphorylation of linker for activation of T cells and ERK upon activation. Normal TCR levels and cytokine production were restored by culturing cells in the absence of TCR/spMHC interaction, demonstrating dynamic tuning of peripheral T cell responses. The effect of avidity for self-ligand(s) on this sensory adaptation was studied by expressing ZAP-YEEI in P14 or HY TCR transgenic backgrounds. Unexpectedly, double-transgenic animals expressed ZAP-YEEI prematurely in double-positive thymocytes, but no overt alteration of selection processes was observed. Instead, modifications of TCR and CD5 expression due to ZAP-YEEI suggested that signal tuning occurred during thymic maturation. Importantly, although P14 x ZAP-YEEI peripheral CD8 T cells were reduced in number and showed lower Ag-induced cytokine production and limited lymphopenia-driven proliferation, the peripheral survival/expansion and Ag responsiveness of HY x ZAP-YEEI cells were enhanced. Our data provide support for central and peripheral sensory T cell adaptation induced as a function of TCR avidity for self-ligands and signaling level. This may contribute to buffer excessive autoreactivity while optimizing TCR repertoire usage. |
| spellingShingle | Marquez, M Ellmeier, W Sanchez-Guajardo, V Freitas, A Acuto, O Di Bartolo, V CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens. |
| title | CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens. |
| title_full | CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens. |
| title_fullStr | CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens. |
| title_full_unstemmed | CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens. |
| title_short | CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens. |
| title_sort | cd8 t cell sensory adaptation dependent on tcr avidity for self antigens |
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