Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres
The selection of high-affinity B cells and the production of high-affinity antibodies are mediated by T follicular helper cells (Tfhs) within germinal centres (GCs). Therein, somatic hypermutation and selection enhance B cell affinity but risk the emergence of self-reactive B cell clones. Despite be...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1253704/full |
| _version_ | 1797674027171446784 |
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| author | Marta Schips Tanmay Mitra Arnab Bandyopadhyay Michael Meyer-Hermann Michael Meyer-Hermann |
| author_facet | Marta Schips Tanmay Mitra Arnab Bandyopadhyay Michael Meyer-Hermann Michael Meyer-Hermann |
| author_sort | Marta Schips |
| collection | DOAJ |
| description | The selection of high-affinity B cells and the production of high-affinity antibodies are mediated by T follicular helper cells (Tfhs) within germinal centres (GCs). Therein, somatic hypermutation and selection enhance B cell affinity but risk the emergence of self-reactive B cell clones. Despite being outnumbered compared to their helper counterpart, the ablation of T follicular regulatory cells (Tfrs) results in enhanced dissemination of self-reactive antibody-secreting cells (ASCs). The specific mechanisms by which Tfrs exert their regulatory action on self-reactive B cells are largely unknown. We developed computer simulations to investigate how Tfrs regulate either selection or differentiation of B cells to prevent auto-reactivity. We observed that Tfr-induced apoptosis of self-reactive B cells during the selection phase impedes self-reactivity with physiological Tfr numbers, especially when Tfrs can access centrocyte-enriched GC areas. While this aided in selecting non-self-reactive B cells by restraining competition, higher Tfr numbers distracted non-self-reactive B cells from receiving survival signals from Tfhs. Thus, the location and number of Tfrs must be regulated to circumvent such Tfr distraction and avoid disrupting GC evolution. In contrast, when Tfrs regulate differentiation of selected centrocytes by promoting recycling to the dark zone phenotype of self-reactive GC resident pre-plasma cells (GCPCs), higher Tfr numbers were required to impede the circulation of self-reactive ASCs (s–ASCs). On the other hand, Tfr-engagement with GCPCs and subsequent apoptosis of s–ASCs can control self-reactivity with low Tfr numbers, but does not confer selection advantage to non-self-reactive B cells. The simulations predict that to restrict auto-reactivity, natural redemption of self-reactive B cells is insufficient and that Tfrs should increase the mutation probability of self-reactive B cells. |
| first_indexed | 2024-03-11T21:54:15Z |
| format | Article |
| id | doaj.art-f2bf46eedb59447aba06618911ecd49a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T21:54:15Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f2bf46eedb59447aba06618911ecd49a2023-09-26T06:10:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-09-011410.3389/fimmu.2023.12537041253704Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centresMarta Schips0Tanmay Mitra1Arnab Bandyopadhyay2Michael Meyer-Hermann3Michael Meyer-Hermann4Department of Systems Immunology, Helmholtz Center for Infection Research, Helmholtz Association of German Research Centers (HZI), Braunschweig, GermanyDepartment of Systems Immunology, Helmholtz Center for Infection Research, Helmholtz Association of German Research Centers (HZI), Braunschweig, GermanyDepartment of Systems Immunology, Helmholtz Center for Infection Research, Helmholtz Association of German Research Centers (HZI), Braunschweig, GermanyDepartment of Systems Immunology, Helmholtz Center for Infection Research, Helmholtz Association of German Research Centers (HZI), Braunschweig, GermanyInstitut für Biochemie, Biotechnologie und Bioinformatik, Technische Universitat Braunschweig, Braunschweig, GermanyThe selection of high-affinity B cells and the production of high-affinity antibodies are mediated by T follicular helper cells (Tfhs) within germinal centres (GCs). Therein, somatic hypermutation and selection enhance B cell affinity but risk the emergence of self-reactive B cell clones. Despite being outnumbered compared to their helper counterpart, the ablation of T follicular regulatory cells (Tfrs) results in enhanced dissemination of self-reactive antibody-secreting cells (ASCs). The specific mechanisms by which Tfrs exert their regulatory action on self-reactive B cells are largely unknown. We developed computer simulations to investigate how Tfrs regulate either selection or differentiation of B cells to prevent auto-reactivity. We observed that Tfr-induced apoptosis of self-reactive B cells during the selection phase impedes self-reactivity with physiological Tfr numbers, especially when Tfrs can access centrocyte-enriched GC areas. While this aided in selecting non-self-reactive B cells by restraining competition, higher Tfr numbers distracted non-self-reactive B cells from receiving survival signals from Tfhs. Thus, the location and number of Tfrs must be regulated to circumvent such Tfr distraction and avoid disrupting GC evolution. In contrast, when Tfrs regulate differentiation of selected centrocytes by promoting recycling to the dark zone phenotype of self-reactive GC resident pre-plasma cells (GCPCs), higher Tfr numbers were required to impede the circulation of self-reactive ASCs (s–ASCs). On the other hand, Tfr-engagement with GCPCs and subsequent apoptosis of s–ASCs can control self-reactivity with low Tfr numbers, but does not confer selection advantage to non-self-reactive B cells. The simulations predict that to restrict auto-reactivity, natural redemption of self-reactive B cells is insufficient and that Tfrs should increase the mutation probability of self-reactive B cells.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1253704/fullT follicular regulatory cellsgerminal centreself-reactivityauto-antibodyagent-based modelmathematical modeling |
| spellingShingle | Marta Schips Tanmay Mitra Arnab Bandyopadhyay Michael Meyer-Hermann Michael Meyer-Hermann Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres Frontiers in Immunology T follicular regulatory cells germinal centre self-reactivity auto-antibody agent-based model mathematical modeling |
| title | Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres |
| title_full | Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres |
| title_fullStr | Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres |
| title_full_unstemmed | Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres |
| title_short | Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres |
| title_sort | suppressive might of a few t follicular regulatory cells impede auto reactivity despite being outnumbered in the germinal centres |
| topic | T follicular regulatory cells germinal centre self-reactivity auto-antibody agent-based model mathematical modeling |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1253704/full |
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