Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions
<jats:p> T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
The Royal Society
2021
|
| Online Access: | https://hdl.handle.net/1721.1/135734 |
| _version_ | 1826201823478808576 |
|---|---|
| author | Swee, Lee Kim Tan, Zhen Wei Sanecka, Anna Yoshida, Nagisa Patel, Harshil Grotenbreg, Gijsbert Frickel, Eva-Maria Ploegh, Hidde L |
| author_facet | Swee, Lee Kim Tan, Zhen Wei Sanecka, Anna Yoshida, Nagisa Patel, Harshil Grotenbreg, Gijsbert Frickel, Eva-Maria Ploegh, Hidde L |
| author_sort | Swee, Lee Kim |
| collection | MIT |
| description | <jats:p>
T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity—hence reactivity to self—and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2
<jats:sup>b</jats:sup>
haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 L
<jats:sup>d</jats:sup>
-restricted epitope, derived from the Rop7 protein of
<jats:italic>Toxoplasma gondii</jats:italic>
. We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon
<jats:italic>Toxoplasma gondii</jats:italic>
infection as well as effector function and TCR signalling upon antigenic stimulation
<jats:italic>in vitro</jats:italic>
. Antigen-independent TCR cross-linking
<jats:italic>in vitro</jats:italic>
uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds.
</jats:p> |
| first_indexed | 2024-09-23T11:57:28Z |
| format | Article |
| id | mit-1721.1/135734 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:57:28Z |
| publishDate | 2021 |
| publisher | The Royal Society |
| record_format | dspace |
| spelling | mit-1721.1/1357342022-04-01T16:26:06Z Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions Swee, Lee Kim Tan, Zhen Wei Sanecka, Anna Yoshida, Nagisa Patel, Harshil Grotenbreg, Gijsbert Frickel, Eva-Maria Ploegh, Hidde L <jats:p> T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity—hence reactivity to self—and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2 <jats:sup>b</jats:sup> haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 L <jats:sup>d</jats:sup> -restricted epitope, derived from the Rop7 protein of <jats:italic>Toxoplasma gondii</jats:italic> . We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon <jats:italic>Toxoplasma gondii</jats:italic> infection as well as effector function and TCR signalling upon antigenic stimulation <jats:italic>in vitro</jats:italic> . Antigen-independent TCR cross-linking <jats:italic>in vitro</jats:italic> uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds. </jats:p> 2021-10-27T20:29:02Z 2021-10-27T20:29:02Z 2016 2019-05-14T12:24:07Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135734 Swee, L. K., et al. "Peripheral Self-Reactivity Regulates Antigen-Specific Cd8 T-Cell Responses and Cell Division under Physiological Conditions." Open Biol 6 11 (2016). en 10.1098/RSOB.160293 Open Biology Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf The Royal Society Open Biology |
| spellingShingle | Swee, Lee Kim Tan, Zhen Wei Sanecka, Anna Yoshida, Nagisa Patel, Harshil Grotenbreg, Gijsbert Frickel, Eva-Maria Ploegh, Hidde L Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions |
| title | Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions |
| title_full | Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions |
| title_fullStr | Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions |
| title_full_unstemmed | Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions |
| title_short | Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions |
| title_sort | peripheral self reactivity regulates antigen specific cd8 t cell responses and cell division under physiological conditions |
| url | https://hdl.handle.net/1721.1/135734 |
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