Redox regulation of age-associated defects in generation and maintenance of T cell self-tolerance and immunity to foreign antigens

Allison K. Hester; Manpreet K. Semwal; Sergio Cepeda; Yangming Xiao; Meghan Rueda; Kymberly Wimberly; Thomas Venables; Thamotharampillai Dileepan; Ellen Kraig; Ann V. Griffith

doi:10.1016/j.celrep.2022.110363

Redox regulation of age-associated defects in generation and maintenance of T cell self-tolerance and immunity to foreign antigens

Allison K. Hester, Manpreet K. Semwal, Sergio Cepeda, Yangming Xiao, Meghan Rueda, Kymberly Wimberly, Thomas Venables, Thamotharampillai Dileepan, Ellen Kraig, Ann V. Griffith

Microbiology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.

Original language	English (US)
Article number	110363
Journal	Cell reports
Volume	38
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2022.110363
State	Published - Feb 15 2022

Bibliographical note

Funding Information:
We thank Dr. Marcia Blackman for helpful advice, the Trudeau Institute for providing the mouse-adapted H1N1 (A/Puerto Rico/8/1934 [PR8]) influenza virus, and the Molecular Biology Core Facility (MBCF) at Trudeau Institute for the production of the NP 366–374 /D b and PA 224–233 /D b tetramers. We thank Dr. Marc Jenkins for MHC class II tetramers and helpful discussions. Data were generated in the Flow Cytometry Shared Resource Facility, which is supported by UT Health San Antonio , NIH-NCI P30 CA054174-20 (CTRC at UTHSCSA ), and UL1 TR001120 ( CTSA grant). Data were also generated in the Bioanalytics and Single-Cell Core at UTHSCSA, which is supported by CPRIT grant ( RP150600 ) and the Office of Vice President of Research, UTHSCSA. New microarray data were generated at the Microarray core at University of Texas Southwestern (UTSW). This work was supported by PHS grants R01AI121367 and R56AI153626 , by the Conklyn Family Endowment in Autoimmune Research, and by funds from the UT Health San Antonio to A.V.G. A.K.H. was supported by PHS grants R01AI121367-04S1 , R25GM095480 , and T32AI138944 . This work was supported in part by a grant to UT Health San Antonio from the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program (S.C.) and pilot funding under grant P30AG013319 , San Antonio Nathan Shock Center . M.R. is supported by the IRACDA award K12 GM11 1726 and by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR002647 .

Funding Information:
We thank Dr. Marcia Blackman for helpful advice, the Trudeau Institute for providing the mouse-adapted H1N1 (A/Puerto Rico/8/1934 [PR8]) influenza virus, and the Molecular Biology Core Facility (MBCF) at Trudeau Institute for the production of the NP366?374/Db and PA224?233/Db tetramers. We thank Dr. Marc Jenkins for MHC class II tetramers and helpful discussions. Data were generated in the Flow Cytometry Shared Resource Facility, which is supported by UT Health San Antonio, NIH-NCI P30 CA054174-20 (CTRC at UTHSCSA), and UL1 TR001120 (CTSA grant). Data were also generated in the Bioanalytics and Single-Cell Core at UTHSCSA, which is supported by CPRIT grant (RP150600) and the Office of Vice President of Research, UTHSCSA. New microarray data were generated at the Microarray core at University of Texas Southwestern (UTSW). This work was supported by PHS grants R01AI121367 and R56AI153626, by the Conklyn Family Endowment in Autoimmune Research, and by funds from the UT Health San Antonio to A.V.G. A.K.H. was supported by PHS grants R01AI121367-04S1, R25GM095480, and T32AI138944. This work was supported in part by a grant to UT Health San Antonio from the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program (S.C.) and pilot funding under grant P30AG013319, San Antonio Nathan Shock Center. M.R. is supported by the IRACDA award K12 GM11 1726 and by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR002647. Conceptualization, A.V.G. A.K.H. and M.K.S.; investigations, A.K.H. M.K.S. S.C. Y.X. M.R. K.W. and T.V.; formal analysis, A.K.H. M.K.S. S.C. Y.X. M.R. T.V. and A.V.G.; resources, T.D. and T.V.; writing ? original draft, A.V.G. and E.K.; writing ? review & editing, A.K.H. M.K.S. S.C. Y.X. M.R. K.W. T.V. T.D. E.K. and A.V.G.; funding acquisition and supervision, E.K. and A.V.G. The authors declare no competing interests.

Publisher Copyright:
© 2022 The Author(s)

Keywords

autoimmunity
central tolerance
immunosenescence
thymus

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1016/j.celrep.2022.110363

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@article{fc845217fd11448b812cb8271fe0e77a,

title = "Redox regulation of age-associated defects in generation and maintenance of T cell self-tolerance and immunity to foreign antigens",

abstract = "Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.",

keywords = "autoimmunity, central tolerance, immunosenescence, thymus",

author = "Hester, {Allison K.} and Semwal, {Manpreet K.} and Sergio Cepeda and Yangming Xiao and Meghan Rueda and Kymberly Wimberly and Thomas Venables and Thamotharampillai Dileepan and Ellen Kraig and Griffith, {Ann V.}",

note = "Funding Information: We thank Dr. Marcia Blackman for helpful advice, the Trudeau Institute for providing the mouse-adapted H1N1 (A/Puerto Rico/8/1934 [PR8]) influenza virus, and the Molecular Biology Core Facility (MBCF) at Trudeau Institute for the production of the NP 366–374 /D b and PA 224–233 /D b tetramers. We thank Dr. Marc Jenkins for MHC class II tetramers and helpful discussions. Data were generated in the Flow Cytometry Shared Resource Facility, which is supported by UT Health San Antonio , NIH-NCI P30 CA054174-20 (CTRC at UTHSCSA ), and UL1 TR001120 ( CTSA grant). Data were also generated in the Bioanalytics and Single-Cell Core at UTHSCSA, which is supported by CPRIT grant ( RP150600 ) and the Office of Vice President of Research, UTHSCSA. New microarray data were generated at the Microarray core at University of Texas Southwestern (UTSW). This work was supported by PHS grants R01AI121367 and R56AI153626 , by the Conklyn Family Endowment in Autoimmune Research, and by funds from the UT Health San Antonio to A.V.G. A.K.H. was supported by PHS grants R01AI121367-04S1 , R25GM095480 , and T32AI138944 . This work was supported in part by a grant to UT Health San Antonio from the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program (S.C.) and pilot funding under grant P30AG013319 , San Antonio Nathan Shock Center . M.R. is supported by the IRACDA award K12 GM11 1726 and by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR002647 . Funding Information: We thank Dr. Marcia Blackman for helpful advice, the Trudeau Institute for providing the mouse-adapted H1N1 (A/Puerto Rico/8/1934 [PR8]) influenza virus, and the Molecular Biology Core Facility (MBCF) at Trudeau Institute for the production of the NP366?374/Db and PA224?233/Db tetramers. We thank Dr. Marc Jenkins for MHC class II tetramers and helpful discussions. Data were generated in the Flow Cytometry Shared Resource Facility, which is supported by UT Health San Antonio, NIH-NCI P30 CA054174-20 (CTRC at UTHSCSA), and UL1 TR001120 (CTSA grant). Data were also generated in the Bioanalytics and Single-Cell Core at UTHSCSA, which is supported by CPRIT grant (RP150600) and the Office of Vice President of Research, UTHSCSA. New microarray data were generated at the Microarray core at University of Texas Southwestern (UTSW). This work was supported by PHS grants R01AI121367 and R56AI153626, by the Conklyn Family Endowment in Autoimmune Research, and by funds from the UT Health San Antonio to A.V.G. A.K.H. was supported by PHS grants R01AI121367-04S1, R25GM095480, and T32AI138944. This work was supported in part by a grant to UT Health San Antonio from the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program (S.C.) and pilot funding under grant P30AG013319, San Antonio Nathan Shock Center. M.R. is supported by the IRACDA award K12 GM11 1726 and by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR002647. Conceptualization, A.V.G. A.K.H. and M.K.S.; investigations, A.K.H. M.K.S. S.C. Y.X. M.R. K.W. and T.V.; formal analysis, A.K.H. M.K.S. S.C. Y.X. M.R. T.V. and A.V.G.; resources, T.D. and T.V.; writing ? original draft, A.V.G. and E.K.; writing ? review & editing, A.K.H. M.K.S. S.C. Y.X. M.R. K.W. T.V. T.D. E.K. and A.V.G.; funding acquisition and supervision, E.K. and A.V.G. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = feb,

day = "15",

doi = "10.1016/j.celrep.2022.110363",

language = "English (US)",

volume = "38",

journal = "Cell Reports",

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T1 - Redox regulation of age-associated defects in generation and maintenance of T cell self-tolerance and immunity to foreign antigens

AU - Hester, Allison K.

AU - Semwal, Manpreet K.

AU - Cepeda, Sergio

AU - Xiao, Yangming

AU - Rueda, Meghan

AU - Wimberly, Kymberly

AU - Venables, Thomas

AU - Dileepan, Thamotharampillai

AU - Kraig, Ellen

AU - Griffith, Ann V.

N1 - Funding Information: We thank Dr. Marcia Blackman for helpful advice, the Trudeau Institute for providing the mouse-adapted H1N1 (A/Puerto Rico/8/1934 [PR8]) influenza virus, and the Molecular Biology Core Facility (MBCF) at Trudeau Institute for the production of the NP 366–374 /D b and PA 224–233 /D b tetramers. We thank Dr. Marc Jenkins for MHC class II tetramers and helpful discussions. Data were generated in the Flow Cytometry Shared Resource Facility, which is supported by UT Health San Antonio , NIH-NCI P30 CA054174-20 (CTRC at UTHSCSA ), and UL1 TR001120 ( CTSA grant). Data were also generated in the Bioanalytics and Single-Cell Core at UTHSCSA, which is supported by CPRIT grant ( RP150600 ) and the Office of Vice President of Research, UTHSCSA. New microarray data were generated at the Microarray core at University of Texas Southwestern (UTSW). This work was supported by PHS grants R01AI121367 and R56AI153626 , by the Conklyn Family Endowment in Autoimmune Research, and by funds from the UT Health San Antonio to A.V.G. A.K.H. was supported by PHS grants R01AI121367-04S1 , R25GM095480 , and T32AI138944 . This work was supported in part by a grant to UT Health San Antonio from the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program (S.C.) and pilot funding under grant P30AG013319 , San Antonio Nathan Shock Center . M.R. is supported by the IRACDA award K12 GM11 1726 and by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR002647 . Funding Information: We thank Dr. Marcia Blackman for helpful advice, the Trudeau Institute for providing the mouse-adapted H1N1 (A/Puerto Rico/8/1934 [PR8]) influenza virus, and the Molecular Biology Core Facility (MBCF) at Trudeau Institute for the production of the NP366?374/Db and PA224?233/Db tetramers. We thank Dr. Marc Jenkins for MHC class II tetramers and helpful discussions. Data were generated in the Flow Cytometry Shared Resource Facility, which is supported by UT Health San Antonio, NIH-NCI P30 CA054174-20 (CTRC at UTHSCSA), and UL1 TR001120 (CTSA grant). Data were also generated in the Bioanalytics and Single-Cell Core at UTHSCSA, which is supported by CPRIT grant (RP150600) and the Office of Vice President of Research, UTHSCSA. New microarray data were generated at the Microarray core at University of Texas Southwestern (UTSW). This work was supported by PHS grants R01AI121367 and R56AI153626, by the Conklyn Family Endowment in Autoimmune Research, and by funds from the UT Health San Antonio to A.V.G. A.K.H. was supported by PHS grants R01AI121367-04S1, R25GM095480, and T32AI138944. This work was supported in part by a grant to UT Health San Antonio from the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program (S.C.) and pilot funding under grant P30AG013319, San Antonio Nathan Shock Center. M.R. is supported by the IRACDA award K12 GM11 1726 and by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR002647. Conceptualization, A.V.G. A.K.H. and M.K.S.; investigations, A.K.H. M.K.S. S.C. Y.X. M.R. K.W. and T.V.; formal analysis, A.K.H. M.K.S. S.C. Y.X. M.R. T.V. and A.V.G.; resources, T.D. and T.V.; writing ? original draft, A.V.G. and E.K.; writing ? review & editing, A.K.H. M.K.S. S.C. Y.X. M.R. K.W. T.V. T.D. E.K. and A.V.G.; funding acquisition and supervision, E.K. and A.V.G. The authors declare no competing interests. Publisher Copyright: © 2022 The Author(s)

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Y1 - 2022/2/15

N2 - Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.

AB - Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.

KW - autoimmunity

KW - central tolerance

KW - immunosenescence

KW - thymus

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JF - Cell Reports

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ER -

Redox regulation of age-associated defects in generation and maintenance of T cell self-tolerance and immunity to foreign antigens

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

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