Effect of cellular aging on memory T-cell homeostasis
The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underl...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.947242/full |
| _version_ | 1828182203132018688 |
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| author | Arpit C. Swain Arpit C. Swain José A.M. Borghans Rob J. de Boer |
| author_facet | Arpit C. Swain Arpit C. Swain José A.M. Borghans Rob J. de Boer |
| author_sort | Arpit C. Swain |
| collection | DOAJ |
| description | The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this ‘homeostatic’ regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, ‘global’ competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional ‘cognate’ competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the ‘gold-standard’. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for ‘cognate’ competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the ‘gold-standard’ level of TCR diversity in the memory T-cell pool. |
| first_indexed | 2024-04-12T06:13:27Z |
| format | Article |
| id | doaj.art-111c5e36ba314aba8dacde36516affa5 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T06:13:27Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-111c5e36ba314aba8dacde36516affa52022-12-22T03:44:35ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-08-011310.3389/fimmu.2022.947242947242Effect of cellular aging on memory T-cell homeostasisArpit C. Swain0Arpit C. Swain1José A.M. Borghans2Rob J. de Boer3Theoretical Biology, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsCenter for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsTheoretical Biology, Utrecht University, Utrecht, NetherlandsThe fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this ‘homeostatic’ regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, ‘global’ competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional ‘cognate’ competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the ‘gold-standard’. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for ‘cognate’ competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the ‘gold-standard’ level of TCR diversity in the memory T-cell pool.https://www.frontiersin.org/articles/10.3389/fimmu.2022.947242/fullhomeostatic regulationT cellmathematical modellingcompetitive exclusionMemory attritioncellular aging |
| spellingShingle | Arpit C. Swain Arpit C. Swain José A.M. Borghans Rob J. de Boer Effect of cellular aging on memory T-cell homeostasis Frontiers in Immunology homeostatic regulation T cell mathematical modelling competitive exclusion Memory attrition cellular aging |
| title | Effect of cellular aging on memory T-cell homeostasis |
| title_full | Effect of cellular aging on memory T-cell homeostasis |
| title_fullStr | Effect of cellular aging on memory T-cell homeostasis |
| title_full_unstemmed | Effect of cellular aging on memory T-cell homeostasis |
| title_short | Effect of cellular aging on memory T-cell homeostasis |
| title_sort | effect of cellular aging on memory t cell homeostasis |
| topic | homeostatic regulation T cell mathematical modelling competitive exclusion Memory attrition cellular aging |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.947242/full |
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