The differentiation of follicular regulatory T cells can be limited by the cytokine IL-2, preventing the emergence of autoantibodies. This research identifies these cells as key regulators of the germinal center response

CG Vinuesa

D Botta

H Wu

I Wollenberg

J Huehn

JB Wing

Kai-Michael Toellner

MA Koch

MA Linterman

Michelle A Linterman

W Pierson

Y Chung

Y Zhang

Linterman, Michelle A

Toellner, Kai-Michael

University of Birmingham Research Portal

  University of BirminghamTFR cells trump autoimmune antibody responses tolimit seditionLinterman, Michelle A; Toellner, Kai-MichaelDOI:10.1038/ni.385610.1038/ni.3856License:Other (please specify with Rights Statement)Document VersionPeer reviewed versionCitation for published version (Harvard):Linterman, MA & Toellner, K-M 2017, 'TFR cells trump autoimmune antibody responses to limit sedition', NatureImmunology, vol. 18, no. 11, pp. 1185-1186. https://doi.org/10.1038/ni.3856, https://doi.org/10.1038/ni.3856Link to publication on Research at Birmingham portalPublisher Rights Statement:Final publication: Nature Immunology 18, 1185–1186 (2017) doi:10.1038/ni.3856 Published online 18 October 2017General rightsUnless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or thecopyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposespermitted by law.•Users may freely distribute the URL that is used to identify this publication.•Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of privatestudy or non-commercial research.•User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?)•Users may not further distribute the material nor use it for the purposes of commercial gain.Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document.When citing, please reference the published version.Take down policyWhile the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has beenuploaded in error or has been deemed to be commercially or otherwise sensitive.If you believe that this is the case for this document, please contact UBIRA@lists.bham.ac.uk providing details and we will remove access tothe work immediately and investigate.Download date: 07. Jan. 2026Tfr cells trump autoimmune antibody responses to limit sedition   Michelle A. Linterman1 & Kai-Michael Toellner2  1. Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK 2. Institute for Immunology and Immunotherapy, University of Birmingham Medical School, Birmingham, UK.  Correspondence to Michelle Linterman: michelle.linterman@babraham.ac.uk  Interleukin 2 inhibits follicular T helper cells and promotes Foxp3-expressing regulatory T cell generation. Ballesteros-Tato and colleagues shows that things are more complex for Tfr cell generation.   Germinal centers (GCs) form in secondary lymphoid tissues after infection or immunization, producing both memory B cells and antibody-secreting plasma cells that provide protection against subsequent infection1. GCs are absolutely dependent on T follicular helper (TFH) cells for their formation and maintenance, and contain a population of Foxp3+ follicular regulatory T (TFR) cells whose biology has remained enigmatic since their discovery in 2011 (ref. 2). In this issue of Nature Immunology, Ballesteros-Tato and colleagues demonstrate an inhibitory role of interleukin 2 (IL-2) in TFR cell differentiation, and show that preventing TFR cell differentiation results in increased production of antibody-secreting plasma cells, including those with self-reactive specificity3.  In contrast to TFH cells, which provide help to GC B cells, TFR cells have a suppressive function and are thought to limit the GC response. Despite their regulatory capacity, TFR cells phenotypically resemble TFH cells, expressing CXCR5, PD-1, and Bcl-6, the transcription factor that is essential for both TFH and TFR cell differentiation4–6. One common feature of both TFH and TFR cells that they do not express CD25, the α chain of the high-affinity interleukin 2 (IL-2) receptor4,7,8. In primed CD4+ T cells signaling via CD25 inhibits Bcl6 expression, thereby preventing TFH cell differentiation2. However, it is not clear why TFR cells do not express CD25; this is especially paradoxical as Foxp3+ regulatory T (Treg) cells require IL-2 signaling for their maintenance. Ballesteros-Tato and colleagues now show that abundance of IL-2 also suppresses TFR cell differentiation (Fig. 1)3. In the context of influenza 1  infection this mechanism delays the differentiation of TFR cells from Foxp3+ precursors until IL-2 concentrations have declined. An inhibitory role of IL-2 on TFR cell formation was recently also reported by another group8. IL-2 suppresses TFH cell development by inducing STAT5 phosphorylation, a mechanism that is dependent on Blimp-1 expression2. Blimp-1 limits the size of the TFR cell population in a cell-intrinsic way4, and, interestingly, enhancing IL-2 availability in Blimp-1-deficient cells does not inhibit TFR cell accumulation, suggesting that an IL-2–STAT5–Blimp-1 axis represses TFR cell differentiation. However, not all Blimp-1-negative Treg cells are TFR cells, indicating that other signals events need to be delivered in parallel with IL-2 withdrawal before a Treg cell is able to become a TFR cell3.       Intriguingly, influenza infection yields IL-2 concentrations sufficient to inhibit TFR, but not TFH, cell differentiation3. This difference in responses to IL-2 may be because TFR cell precursors are more sensitive to IL-2 than TFH precursors, due to higher CD25 expression. CD25 is expressed by the majority of Treg cells and signaling via this receptor is essential for their survival and expansion under homeostatic conditions9. However, like TFR cells, some Treg cells do not express CD25; Treg cells expressing T-bet, the transcriptional regulator of TH1 cells, and Treg cells with an effector/memory phenotype have also down-regulated CD25 expression10,11. Taken together, these studies may intimate a model in which “naïve” Treg cells require IL-2 signaling for their maintenance, but that limiting IL-2 signaling is essential for Treg cells to differentiate into effector subsets or memory Treg cells.   The role that TFR cells play in GC biology has been difficult to decipher, with multiple studies yielding conflicting results. Initially this was because there was no mouse model that specifically lacked TFR cells. Because of this, all in vivo experiments were performed using mixed bone marrow chimeras or adoptive cell transfers, systems which have limitations. The generation of Bcl6flox/floxFoxp3cre animals provides a mouse that specifically lacks TFR cells12. Ballesteros-Tato and colleagues3 use this model to demonstrate TFR cells control the formation of antibody-secreting cells. This dysregulation in the absence of TFR cells is not simply due to a change in magnitude of the response, as the antibody specificity is also altered: lack of TFR cells does not alter anti-influenza antibody titer, but increases production of anti-nuclear autoimmune antibodies after influenza infection. Consistent with the role 2  of IL-2 in limiting TFR cell formation, treating mice with recombinant IL-2 also results in autoantibody production3.   The finding that TFR cells limit the production of self-reactive antibody-secreting plasma cells is a key discovery in understanding the biology of these cells. Within the GC, B cells undergo somatic hypermutation of the genes encoding their B cell receptors. This mutation process is random and can result in the emergence of self-reactive clones. It is, therefore, essential that the selection of mutated GC B cells is stringent, in order to ensure these cells do not exit the GC as long-lived plasma cells or memory B cells. Selection within the GC is a process thought to be driven through positive feedback to B cells from follicular dendritic cells and TFH cells, while self-reactive B cells perish through neglect1. The discovery that, in the absence of TFR cells, B cells with a self-reactive B cell receptor can emerge from the GC suggests that these cells may have an active role in negative B cell selection. Alternatively, TFR cells may act to limit the provision of positive signals from either TFH cells or follicular dendritic cells. The mechanism by which TFR cells control autoreactivity from the GC, and the main cell types on whom they act are pertinent questions in understanding not just the role for TFR cells, but the biology of the GC.   Legend to Figure 1 When IL-2 binds the high affinity IL-2 receptor, composed of CD122, the common γ chain (γc) and CD25, STAT5 is phosphorylated leading to repression of Bcl6, and increase in Blimp1 expression. The lack of Bcl6 and increase in Blimp1 inhibits Tfr cell differentiation in Foxp3+ precursors.   References 1. Zhang, Y., Garcia-Ibanez, L. & Toellner, K.M. Immunol. Rev. 270, 8–19 (2016). doi: 10.1111/imr.12396. 2. Vinuesa, C.G., Linterman, M.A., Yu, D. & MacLennan, IC. Annu. Rev Immunol. 34, 335–368 (2016). doi: 10.1146/annurev-immunol-041015-055605. 3. Botta, D. et al. Nat. Immunol. 18, XXX–XXX (2017). 4. Linterman, M.A. et al. Nat. Med. 17, 975–982 (2011). doi: 10.1038/nm.2425. 5. Chung, Y. et al. Nat. Med. 17, 983–988 (2011). doi: 10.1038/nm.2426 6. Wollenberg, I. et al. J. Immunol. 187, 4553–4560 (2011). doi: 10.4049/jimmunol.1101328. 3  7. Wing, J.B. et al. Proc. Natl. Acad. Sci. USA 114, E6400-E6409 (2017). doi: 10.1073/pnas.1705551114. 8. Ritvo, P.G. et al. Sci. Immunol. (8 September 2017) 2(15). pii: eaan0368. 9. Pierson, W. et al.  Nat. Immunol. 14, 959–965 (2013). doi: 10.1038/ni.2649. 10. Koch, M.A. et al.  Nat. Immunol. 10, 595–602 (2009). doi: 10.1038/ni.1731. 11. Huehn, J. et al. J. Exp. Med. 199, 303–313 (2004). 12. Wu, H. et al. Eur. J. Immunol. 46, 1152–1161 (2016). doi: 10.1002/eji.201546094.   4  

English

TFR cells trump autoimmune antibody responses to limit sedition

Crossref

Nature Immunology

  University of BirminghamTFR cells trump autoimmune antibody responses tolimit seditionLinterman, Michelle A; Toellner, Kai-MichaelDOI:10.1038/ni.385610.1038/ni.3856License:Other (please specify with Rights Statement)Document VersionPeer reviewed versionCitation for published version (Harvard):Linterman, MA & Toellner, K-M 2017, 'TFR cells trump autoimmune antibody responses to limit sedition', NatureImmunology, vol. 18, no. 11, pp. 1185-1186. https://doi.org/10.1038/ni.3856, https://doi.org/10.1038/ni.3856Link to publication on Research at Birmingham portalPublisher Rights Statement:Final publication: Nature Immunology 18, 1185–1186 (2017) doi:10.1038/ni.3856 Published online 18 October 2017General rightsUnless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or thecopyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposespermitted by law.•	Users may freely distribute the URL that is used to identify this publication.•	Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of privatestudy or non-commercial research.•	User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?)•	Users may not further distribute the material nor use it for the purposes of commercial gain.Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document.When citing, please reference the published version.Take down policyWhile the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has beenuploaded in error or has been deemed to be commercially or otherwise sensitive.If you believe that this is the case for this document, please contact UBIRA@lists.bham.ac.uk providing details and we will remove access tothe work immediately and investigate.Download date: 01. Mar. 2020Tfr cells trump autoimmune antibody responses to limit sedition   Michelle A. Linterman1 & Kai-Michael Toellner2  1. Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK 2. Institute for Immunology and Immunotherapy, University of Birmingham Medical School, Birmingham, UK.  Correspondence to Michelle Linterman: michelle.linterman@babraham.ac.uk  Interleukin 2 inhibits follicular T helper cells and promotes Foxp3-expressing regulatory T cell generation. Ballesteros-Tato and colleagues shows that things are more complex for Tfr cell generation.   Germinal centers (GCs) form in secondary lymphoid tissues after infection or immunization, producing both memory B cells and antibody-secreting plasma cells that provide protection against subsequent infection1. GCs are absolutely dependent on T follicular helper (TFH) cells for their formation and maintenance, and contain a population of Foxp3+ follicular regulatory T (TFR) cells whose biology has remained enigmatic since their discovery in 2011 (ref. 2). In this issue of Nature Immunology, Ballesteros-Tato and colleagues demonstrate an inhibitory role of interleukin 2 (IL-2) in TFR cell differentiation, and show that preventing TFR cell differentiation results in increased production of antibody-secreting plasma cells, including those with self-reactive specificity3.  In contrast to TFH cells, which provide help to GC B cells, TFR cells have a suppressive function and are thought to limit the GC response. Despite their regulatory capacity, TFR cells phenotypically resemble TFH cells, expressing CXCR5, PD-1, and Bcl-6, the transcription factor that is essential for both TFH and TFR cell differentiation4–6. One common feature of both TFH and TFR cells that they do not express CD25, the α chain of the high-affinity interleukin 2 (IL-2) receptor4,7,8. In primed CD4+ T cells signaling via CD25 inhibits Bcl6 expression, thereby preventing TFH cell differentiation2. However, it is not clear why TFR cells do not express CD25; this is especially paradoxical as Foxp3+ regulatory T (Treg) cells require IL-2 signaling for their maintenance. Ballesteros-Tato and colleagues now show that abundance of IL-2 also suppresses TFR cell differentiation (Fig. 1)3. In the context of influenza 1  infection this mechanism delays the differentiation of TFR cells from Foxp3+ precursors until IL-2 concentrations have declined. An inhibitory role of IL-2 on TFR cell formation was recently also reported by another group8. IL-2 suppresses TFH cell development by inducing STAT5 phosphorylation, a mechanism that is dependent on Blimp-1 expression2. Blimp-1 limits the size of the TFR cell population in a cell-intrinsic way4, and, interestingly, enhancing IL-2 availability in Blimp-1-deficient cells does not inhibit TFR cell accumulation, suggesting that an IL-2–STAT5–Blimp-1 axis represses TFR cell differentiation. However, not all Blimp-1-negative Treg cells are TFR cells, indicating that other signals events need to be delivered in parallel with IL-2 withdrawal before a Treg cell is able to become a TFR cell3.       Intriguingly, influenza infection yields IL-2 concentrations sufficient to inhibit TFR, but not TFH, cell differentiation3. This difference in responses to IL-2 may be because TFR cell precursors are more sensitive to IL-2 than TFH precursors, due to higher CD25 expression. CD25 is expressed by the majority of Treg cells and signaling via this receptor is essential for their survival and expansion under homeostatic conditions9. However, like TFR cells, some Treg cells do not express CD25; Treg cells expressing T-bet, the transcriptional regulator of TH1 cells, and Treg cells with an effector/memory phenotype have also down-regulated CD25 expression10,11. Taken together, these studies may intimate a model in which “naïve” Treg cells require IL-2 signaling for their maintenance, but that limiting IL-2 signaling is essential for Treg cells to differentiate into effector subsets or memory Treg cells.   The role that TFR cells play in GC biology has been difficult to decipher, with multiple studies yielding conflicting results. Initially this was because there was no mouse model that specifically lacked TFR cells. Because of this, all in vivo experiments were performed using mixed bone marrow chimeras or adoptive cell transfers, systems which have limitations. The generation of Bcl6flox/floxFoxp3cre animals provides a mouse that specifically lacks TFR cells12. Ballesteros-Tato and colleagues3 use this model to demonstrate TFR cells control the formation of antibody-secreting cells. This dysregulation in the absence of TFR cells is not simply due to a change in magnitude of the response, as the antibody specificity is also altered: lack of TFR cells does not alter anti-influenza antibody titer, but increases production of anti-nuclear autoimmune antibodies after influenza infection. Consistent with the role 2  of IL-2 in limiting TFR cell formation, treating mice with recombinant IL-2 also results in autoantibody production3.   The finding that TFR cells limit the production of self-reactive antibody-secreting plasma cells is a key discovery in understanding the biology of these cells. Within the GC, B cells undergo somatic hypermutation of the genes encoding their B cell receptors. This mutation process is random and can result in the emergence of self-reactive clones. It is, therefore, essential that the selection of mutated GC B cells is stringent, in order to ensure these cells do not exit the GC as long-lived plasma cells or memory B cells. Selection within the GC is a process thought to be driven through positive feedback to B cells from follicular dendritic cells and TFH cells, while self-reactive B cells perish through neglect1. The discovery that, in the absence of TFR cells, B cells with a self-reactive B cell receptor can emerge from the GC suggests that these cells may have an active role in negative B cell selection. Alternatively, TFR cells may act to limit the provision of positive signals from either TFH cells or follicular dendritic cells. The mechanism by which TFR cells control autoreactivity from the GC, and the main cell types on whom they act are pertinent questions in understanding not just the role for TFR cells, but the biology of the GC.   Legend to Figure 1 When IL-2 binds the high affinity IL-2 receptor, composed of CD122, the common γ chain (γc) and CD25, STAT5 is phosphorylated leading to repression of Bcl6, and increase in Blimp1 expression. The lack of Bcl6 and increase in Blimp1 inhibits Tfr cell differentiation in Foxp3+ precursors.   References 1. Zhang, Y., Garcia-Ibanez, L. & Toellner, K.M. Immunol. Rev. 270, 8–19 (2016). doi: 10.1111/imr.12396. 2. Vinuesa, C.G., Linterman, M.A., Yu, D. & MacLennan, IC. Annu. Rev Immunol. 34, 335–368 (2016). doi: 10.1146/annurev-immunol-041015-055605. 3. Botta, D. et al. Nat. Immunol. 18, XXX–XXX (2017). 4. Linterman, M.A. et al. Nat. Med. 17, 975–982 (2011). doi: 10.1038/nm.2425. 5. Chung, Y. et al. Nat. Med. 17, 983–988 (2011). doi: 10.1038/nm.2426 6. Wollenberg, I. et al. J. Immunol. 187, 4553–4560 (2011). doi: 10.4049/jimmunol.1101328. 3  7. Wing, J.B. et al. Proc. Natl. Acad. Sci. USA 114, E6400-E6409 (2017). doi: 10.1073/pnas.1705551114. 8. Ritvo, P.G. et al. Sci. Immunol. (8 September 2017) 2(15). pii: eaan0368. 9. Pierson, W. et al.  Nat. Immunol. 14, 959–965 (2013). doi: 10.1038/ni.2649. 10. Koch, M.A. et al.  Nat. Immunol. 10, 595–602 (2009). doi: 10.1038/ni.1731. 11. Huehn, J. et al. J. Exp. Med. 199, 303–313 (2004). 12. Wu, H. et al. Eur. J. Immunol. 46, 1152–1161 (2016). doi: 10.1002/eji.201546094.   4  

  TFR cells trump autoimmune antibody responses tolimit seditionLinterman, Michelle A; Toellner, Kai-MichaelDOI:10.1038/ni.385610.1038/ni.3856License:Other (please specify with Rights Statement)Document VersionPeer reviewed versionCitation for published version (Harvard):Linterman, MA & Toellner, K-M 2017, 'TFR cells trump autoimmune antibody responses to limit sedition', NatureImmunology, vol. 18, no. 11, pp. 1185-1186. https://doi.org/10.1038/ni.3856, https://doi.org/10.1038/ni.3856Link to publication on Research at Birmingham portalPublisher Rights Statement:Final publication: Nature Immunology 18, 1185–1186 (2017) doi:10.1038/ni.3856 Published online 18 October 2017General rightsUnless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or thecopyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposespermitted by law.•	Users may freely distribute the URL that is used to identify this publication.•	Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of privatestudy or non-commercial research.•	User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?)•	Users may not further distribute the material nor use it for the purposes of commercial gain.Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document.When citing, please reference the published version.Take down policyWhile the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has beenuploaded in error or has been deemed to be commercially or otherwise sensitive.If you believe that this is the case for this document, please contact UBIRA@lists.bham.ac.uk providing details and we will remove access tothe work immediately and investigate.Download date: 01. Feb. 2019Tfr cells trump autoimmune antibody responses to limit sedition   Michelle A. Linterman1 & Kai-Michael Toellner2  1. Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK 2. Institute for Immunology and Immunotherapy, University of Birmingham Medical School, Birmingham, UK.  Correspondence to Michelle Linterman: michelle.linterman@babraham.ac.uk  Interleukin 2 inhibits follicular T helper cells and promotes Foxp3-expressing regulatory T cell generation. Ballesteros-Tato and colleagues shows that things are more complex for Tfr cell generation.   Germinal centers (GCs) form in secondary lymphoid tissues after infection or immunization, producing both memory B cells and antibody-secreting plasma cells that provide protection against subsequent infection1. GCs are absolutely dependent on T follicular helper (TFH) cells for their formation and maintenance, and contain a population of Foxp3+ follicular regulatory T (TFR) cells whose biology has remained enigmatic since their discovery in 2011 (ref. 2). In this issue of Nature Immunology, Ballesteros-Tato and colleagues demonstrate an inhibitory role of interleukin 2 (IL-2) in TFR cell differentiation, and show that preventing TFR cell differentiation results in increased production of antibody-secreting plasma cells, including those with self-reactive specificity3.  In contrast to TFH cells, which provide help to GC B cells, TFR cells have a suppressive function and are thought to limit the GC response. Despite their regulatory capacity, TFR cells phenotypically resemble TFH cells, expressing CXCR5, PD-1, and Bcl-6, the transcription factor that is essential for both TFH and TFR cell differentiation4–6. One common feature of both TFH and TFR cells that they do not express CD25, the α chain of the high-affinity interleukin 2 (IL-2) receptor4,7,8. In primed CD4+ T cells signaling via CD25 inhibits Bcl6 expression, thereby preventing TFH cell differentiation2. However, it is not clear why TFR cells do not express CD25; this is especially paradoxical as Foxp3+ regulatory T (Treg) cells require IL-2 signaling for their maintenance. Ballesteros-Tato and colleagues now show that abundance of IL-2 also suppresses TFR cell differentiation (Fig. 1)3. In the context of influenza 1  infection this mechanism delays the differentiation of TFR cells from Foxp3+ precursors until IL-2 concentrations have declined. An inhibitory role of IL-2 on TFR cell formation was recently also reported by another group8. IL-2 suppresses TFH cell development by inducing STAT5 phosphorylation, a mechanism that is dependent on Blimp-1 expression2. Blimp-1 limits the size of the TFR cell population in a cell-intrinsic way4, and, interestingly, enhancing IL-2 availability in Blimp-1-deficient cells does not inhibit TFR cell accumulation, suggesting that an IL-2–STAT5–Blimp-1 axis represses TFR cell differentiation. However, not all Blimp-1-negative Treg cells are TFR cells, indicating that other signals events need to be delivered in parallel with IL-2 withdrawal before a Treg cell is able to become a TFR cell3.       Intriguingly, influenza infection yields IL-2 concentrations sufficient to inhibit TFR, but not TFH, cell differentiation3. This difference in responses to IL-2 may be because TFR cell precursors are more sensitive to IL-2 than TFH precursors, due to higher CD25 expression. CD25 is expressed by the majority of Treg cells and signaling via this receptor is essential for their survival and expansion under homeostatic conditions9. However, like TFR cells, some Treg cells do not express CD25; Treg cells expressing T-bet, the transcriptional regulator of TH1 cells, and Treg cells with an effector/memory phenotype have also down-regulated CD25 expression10,11. Taken together, these studies may intimate a model in which “naïve” Treg cells require IL-2 signaling for their maintenance, but that limiting IL-2 signaling is essential for Treg cells to differentiate into effector subsets or memory Treg cells.   The role that TFR cells play in GC biology has been difficult to decipher, with multiple studies yielding conflicting results. Initially this was because there was no mouse model that specifically lacked TFR cells. Because of this, all in vivo experiments were performed using mixed bone marrow chimeras or adoptive cell transfers, systems which have limitations. The generation of Bcl6flox/floxFoxp3cre animals provides a mouse that specifically lacks TFR cells12. Ballesteros-Tato and colleagues3 use this model to demonstrate TFR cells control the formation of antibody-secreting cells. This dysregulation in the absence of TFR cells is not simply due to a change in magnitude of the response, as the antibody specificity is also altered: lack of TFR cells does not alter anti-influenza antibody titer, but increases production of anti-nuclear autoimmune antibodies after influenza infection. Consistent with the role 2  of IL-2 in limiting TFR cell formation, treating mice with recombinant IL-2 also results in autoantibody production3.   The finding that TFR cells limit the production of self-reactive antibody-secreting plasma cells is a key discovery in understanding the biology of these cells. Within the GC, B cells undergo somatic hypermutation of the genes encoding their B cell receptors. This mutation process is random and can result in the emergence of self-reactive clones. It is, therefore, essential that the selection of mutated GC B cells is stringent, in order to ensure these cells do not exit the GC as long-lived plasma cells or memory B cells. Selection within the GC is a process thought to be driven through positive feedback to B cells from follicular dendritic cells and TFH cells, while self-reactive B cells perish through neglect1. The discovery that, in the absence of TFR cells, B cells with a self-reactive B cell receptor can emerge from the GC suggests that these cells may have an active role in negative B cell selection. Alternatively, TFR cells may act to limit the provision of positive signals from either TFH cells or follicular dendritic cells. The mechanism by which TFR cells control autoreactivity from the GC, and the main cell types on whom they act are pertinent questions in understanding not just the role for TFR cells, but the biology of the GC.   Legend to Figure 1 When IL-2 binds the high affinity IL-2 receptor, composed of CD122, the common γ chain (γc) and CD25, STAT5 is phosphorylated leading to repression of Bcl6, and increase in Blimp1 expression. The lack of Bcl6 and increase in Blimp1 inhibits Tfr cell differentiation in Foxp3+ precursors.   References 1. Zhang, Y., Garcia-Ibanez, L. & Toellner, K.M. Immunol. Rev. 270, 8–19 (2016). doi: 10.1111/imr.12396. 2. Vinuesa, C.G., Linterman, M.A., Yu, D. & MacLennan, IC. Annu. Rev Immunol. 34, 335–368 (2016). doi: 10.1146/annurev-immunol-041015-055605. 3. Botta, D. et al. Nat. Immunol. 18, XXX–XXX (2017). 4. Linterman, M.A. et al. Nat. Med. 17, 975–982 (2011). doi: 10.1038/nm.2425. 5. Chung, Y. et al. Nat. Med. 17, 983–988 (2011). doi: 10.1038/nm.2426 6. Wollenberg, I. et al. J. Immunol. 187, 4553–4560 (2011). doi: 10.4049/jimmunol.1101328. 3  7. Wing, J.B. et al. Proc. Natl. Acad. Sci. USA 114, E6400-E6409 (2017). doi: 10.1073/pnas.1705551114. 8. Ritvo, P.G. et al. Sci. Immunol. (8 September 2017) 2(15). pii: eaan0368. 9. Pierson, W. et al.  Nat. Immunol. 14, 959–965 (2013). doi: 10.1038/ni.2649. 10. Koch, M.A. et al.  Nat. Immunol. 10, 595–602 (2009). doi: 10.1038/ni.1731. 11. Huehn, J. et al. J. Exp. Med. 199, 303–313 (2004). 12. Wu, H. et al. Eur. J. Immunol. 46, 1152–1161 (2016). doi: 10.1002/eji.201546094.   4  

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TFR cells trump autoimmune antibody responses to limit sedition

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