- Email: [email protected]
T cells climb on board Blimp-1
Update
TRENDS in Immunology
Vol.27 No.8
Full text provided by www.sciencedirect.com
Research Focus
T cells climb on board Blimp-1 Stephen C. Jameson Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
B lymphocyte-induced maturation protein (Blimp)-1, a transcriptional repressor, has long been known to drive the terminal maturation of B cells into plasma cells. However, two recent studies reveal an unanticipated role for Blimp-1 in T-cell homeostasis. Blimp-1-deficient T cells exhibit enhanced proliferative and functional responses following activation, and induce spontaneous colitis. Hence, aside from its role in B-cell differentiation, Blimp-1 directs restraint among T cells. Over-viewing Blimp-1 Although immunologists often focus on the differences between T cells and B cells, these cells share several differentiation and regulatory processes. A novel example of this is an unexpected role for B lymphocyte-induced maturation protein (Blimp)-1 in T-cell homeostasis [1,2]. Blimp-1 (also known by its gene name Prdm1) represses the transcription of several genes [including those encoding B-cell lymphoma (Bcl)-6, paired box (Pax)5 and c-myc] that instruct activated B cells to withdraw from the cell cycle and become immunoglobulin-secreting plasma cells [3–7] (Figure 1). Mice containing Blimp-1-deficient B cells fail to produce plasma cells, have low serum immunoglobulin levels and accumulate activated follicular B cells in their germinal centers [4,5]. Although there is no completely analogous stage for plasma cells in T-cell differentiation, they can be compared to a hybrid of memory and effector T cells, based on their advanced maturation state. So, does Blimp-1 also impact later stages of T-cell differentiation? The new studies show it does – but not in the way one might have predicted. Blimp-1 regulates T-cell responses In their reports, the groups of Calame [1] and Nutt [2] used different tactics to circumvent the embryonic lethality associated with Blimp-1 deficiency (which is probably owing to vascular abnormalities resulting in inadequate placental development [8]). Martins et al. used a conditional knockout approach to limit Blimp-1 deletion to T cells [1], whereas Kallies and colleagues employed a gene knockin mutant, with the benefit that Blimp-1 transcription was reported by green fluorescent protein production, allowing the correlation of Blimp-1 expression with phenotypic or functional attributes [2]. Both groups found that Blimp-1-deficiency results in dramatic effects on T-cell homeostasis, manifesting as the accumulation of activated- and memory-phenotype T cells [1,2]. This correlates nicely with the finding of the two groups that Blimp-1 mRNA expression is low in naive Corresponding author: Jameson, S.C. ([email protected]). Available online 27 June 2006 www.sciencedirect.com
T cells, but elevated in memory and effector T cells (in both CD4 and CD8 subsets). Intriguingly, Blimp-1 is upregulated gradually following T-cell stimulation, requiring many days of activation or restimulation to induce maximal expression [1,2]. Given its function in B cells, we might expect Blimp-1 to curtail activated T-cell proliferation. Indeed, both groups find that in vitro-stimulated Blimp-1-deficient T cells expand better than wild-type cells. However, the basis for this effect is less clear. Martins et al. report enhanced proliferation of activated naive Blimp-1-deficient T cells [1], whereas Kallies et al. suggest that naive T-cell expansion is independent of Blimp-1 but that Blimp-1-deficient T cells accumulate following restimulation [2]. Furthermore, Kallies et al. demonstrate that this effect is owing to impaired activation-induced cell death, rather than enhanced proliferation [2]. Future studies must determine whether these differences relate to the Blimp-1deficient models used or simply the details of the in vitro culture systems employed. However, both reports indicate that Blimp-1 restrains the expansion of activated T cells. Kallies et al. also tested anti-viral T-cell responses in vivo, finding that Blimp-1-deficient cells showed normal initial responses but were slightly over-represented at later time points compared with normal T cells, perhaps implying more-efficient memory T-cell generation. Based on its role in plasma-cell differentiation, one might suppose that Blimp-1 would drive effector T-cell differentiation. By contrast, activated Blimp-1-deficient T cells produce more T-helper (Th)1 cytokines [interferon (IFN)-g and interleukin (IL)-2] [1,2]. This is, perhaps, not so unexpected because T-cell proliferation and effector differentiation often occur together, representing an important distinction from the obligatory withdrawal from the cell cycle of plasma cells. Indeed, elevated IL-2 production might explain the enhanced proliferation of Blimp-1deficient T cells stimulated at low density [1]. However, Blimp-1 loss did cause the defective production of IL-10 [1,2], a point discussed later. Together, these reports suggest that Blimp-1 limits T-cell responses. Following normal T-cell activation, Blimp-1 expression might dictate the end of the expansion phase. However, Blimp-1 could be more important in curtailing prolonged T-cell activation by driving cells into apoptosis instead of proliferation (Figure 1). Although this dampening effect might seem counterproductive, Blimp could be crucial for avoiding T-cell immunopathology, as discussed in the next section. Dangerous T cells fly without Blimp-1 The most dramatic effect of T-cell Blimp-1-deficiency is the spontaneous immunopathology reported by both groups
1471-4906/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2006.06.002
350
Update
TRENDS in Immunology Vol.27 No.8
Figure 1. A model for Blimp-1 regulation of T- and B-cell maturation. Blimp-1 expression levels in various subsets are indicated by the color intensity, with gray representing little or no Blimp-1 expression. In certain subsets (three-dimensional shapes), only certain cells might express Blimp-1. In B cells, Blimp-1 is essential for plasma-cell differentiation in primary and recall responses, and might drive the generation of certain memory B-cell subsets. In T cells, Blimp-1 expression increases gradually following activation, and Blimp-1 might restrain the generation of effector and memory populations by limiting proliferation and/or supporting AICD (activationinduced cell death). This might be of greatest importance in situations of prolonged activation, when Blimp-1 could limit the expansion of immunopathological T cells, either directly or indirectly (through Treg-cell populations).
[1,2]. Martins et al. observed progressive colitis, whereas Kallies et al. reported more-rapid and more-widespread lymphocytic infiltrations, correlating with lethal wasting disease. The divergent extent and severity of the disease might reflect the different approaches used, including a potential role for other Blimp-1-deficient hematopoietic cells in the system used by Nutt’s group [2]. Regardless, these data indicate that Blimp-1 is essential for restraining potentially hazardous T cells. How might Blimp-1 regulate colitis? The exuberant expansion of activated Blimp-1-deficient T cells might permit rare self-reactive T cells to become damaging. However, no current study of immunopathological diseases is complete without discussing regulatory T (Treg) cells. As mentioned, Blimp-1-deficient cells show impaired IL-10 production [1,2], an important cytokine for some forms of T-cell suppression [9,10]. Blimp-1 is found in some CD4+CD25+ T cells [1,2], and unpublished data from Rudensky’s lab has directly demonstrated Blimp-1 expression in the CD4+Foxp3+ Treg-cell subset (A. Rudensky, personal communication). However, in the Blimp-1 knockout systems, CD4+CD25+ and CD4+Foxp3+ T cells are generated, and are potent in vitro suppressors [1,2]. By contrast, the in vivo function of Blimp-1-deficient Treg cells is less clear: Kallies and colleagues report the normal function of these cells, whereas Martins et al. report severely impaired www.sciencedirect.com
suppressive activity [1,2]. These differences could relate to the specific colitis model investigated by the two groups (perhaps reflecting the relevance of IL-10 in the suppressive mechanism). Indeed, Calame’s team observe nearnormal suppression by Blimp-1-deficient Tregs when tested by in vivo assays similar to those used by the Nutt group (K. Calame, personal communication). Thus, these data suggest that certain, but not all, T-regulatory mechanisms could be compromised by Blimp-1-deficiency. Regardless of the basis for T-cell immunopathology, its occurrence might explain another discrepancy between the studies [1,2]. Martins et al. report that Blimp-1-deficiency causes the loss of immature CD4+CD8+ double-positive (DP) thymocytes, and suggest that Blimp-1 protects these cells from apoptosis [1]. However, as discussed previously [11], the spontaneous activation of Blimp-1-deficient T cells might offer an alternative explanation, because DP thymocytes are exquisitely susceptible to factors induced by activated T cells. Indeed, the Nutt group has observed reduced thymocyte cellularity with immunopathology progression (S. Nutt, personal communication). Hence, it is too early to tell if the loss of Blimp-1-deficient DP thymocytes is an autonomous effect. Does Blimp-1 regulate common target genes in B and T cells? Bcl-6 is an attractive candidate, because its repression is essential for plasma-cell generation [6] and Bcl-6
Update
TRENDS in Immunology
has been proposed to support memory T-cell generation [12]. However, although Calame’s group showed that Blimp-1-deficient effector-phenotype T cells upregulate Bcl-6, Nutt’s group did not observe this [1,2]. Given the narrow timing of Blimp-1 expression following T-cell stimulation, more-refined analysis might be required to answer this important question. These studies suggest intriguing parallels in the roles of Blimp-1 for B- and T-cell maturation, although, true to the nature of immunologists, the differences will, perhaps, prove even more interesting. Acknowledgements I thank Kathryn Calame, Stephen Nutt and Sasha Rudensky for providing insights and unpublished observations, and Kris Hogquist for critical input.
References 1 Martins, G.A. et al. (2006) Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol. 7, 457–465 2 Kallies, A. et al. (2006) Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat. Immunol. 7, 466–474
Vol.27 No.8
3 Turner, C.A., Jr et al. (1994) Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297–306 4 Kallies, A. et al. (2004) Plasma cell ontogeny defined by quantitative changes in Blimp-1 expression. J. Exp. Med. 200, 967–977 5 Shapiro-Shelef, M. et al. (2003) Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 6 Shapiro-Shelef, M. and Calame, K. (2005) Regulation of plasma-cell development. Nat. Rev. Immunol. 5, 230–242 7 Messika, E.J. et al. (1998) Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development. J. Exp. Med. 188, 515–525 8 Vincent, S.D. et al. (2005) The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells in the mouse. Development 132, 1315–1325 9 Annacker, O. et al. (2003) Interleukin-10 in the regulation of T cellinduced colitis. J. Autoimmun. 20, 277–279 10 von Boehmer, H. (2005) Mechanisms of suppression by suppressor T cells. Nat. Immunol. 6, 338–344 11 Fink, P.J. (2006) T cells join the Blimp-1 brigade. Nat. Immunol. 7, 445–446 12 Ichii, H. et al. (2002) Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells. Nat. Immunol. 3, 558–563
The Midwinter Conference of Immunologists 27-30 January 2007 Asilomar Conference Grounds, Pacific Grove (near Monterey), California, USA http://www.midwconfimmunol.org Chairs: Nilabh Shastri and Steven F. Ziegler This four-day conference will include sessions focusing on the transcriptional control of immunity, inflammatory responses in infection and allergy, inside-out signaling pathways for generating T-cell receptor ligands, the determination of cell fate in the immune system, and autoimmunity. Scheduled speakers include: Laurie H. Glimcher, Dan R. Littman, Sankar Ghosh, Jenny Ting, Stephen T. Smale, Richard M. Locksley, Anne O’Garra, Andrew D. Luster, Peter Cresswell, Mitchell Kronenberg, Sebastian Amigorena, Susan L. Swain, Douglas R. Green, Warren S. Pear, Kristin A. Hogquist, Jeffrey A. Bluestone, Maria-Grazia Roncarolo, Diane Mathis, Matthias von Herrath. The conference is limited to 650 attendees. The program and registration pack will be available in September from the Registrar: Ms Kim Gurney (e-mail: [email protected]). The registration deadline (without a late fee) is Monday 13 November 2006. After this date, contact the Registrar for available spaces.
www.sciencedirect.com
351
TRENDS in Immunology
Vol.27 No.8
Full text provided by www.sciencedirect.com
Research Focus
T cells climb on board Blimp-1 Stephen C. Jameson Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
B lymphocyte-induced maturation protein (Blimp)-1, a transcriptional repressor, has long been known to drive the terminal maturation of B cells into plasma cells. However, two recent studies reveal an unanticipated role for Blimp-1 in T-cell homeostasis. Blimp-1-deficient T cells exhibit enhanced proliferative and functional responses following activation, and induce spontaneous colitis. Hence, aside from its role in B-cell differentiation, Blimp-1 directs restraint among T cells. Over-viewing Blimp-1 Although immunologists often focus on the differences between T cells and B cells, these cells share several differentiation and regulatory processes. A novel example of this is an unexpected role for B lymphocyte-induced maturation protein (Blimp)-1 in T-cell homeostasis [1,2]. Blimp-1 (also known by its gene name Prdm1) represses the transcription of several genes [including those encoding B-cell lymphoma (Bcl)-6, paired box (Pax)5 and c-myc] that instruct activated B cells to withdraw from the cell cycle and become immunoglobulin-secreting plasma cells [3–7] (Figure 1). Mice containing Blimp-1-deficient B cells fail to produce plasma cells, have low serum immunoglobulin levels and accumulate activated follicular B cells in their germinal centers [4,5]. Although there is no completely analogous stage for plasma cells in T-cell differentiation, they can be compared to a hybrid of memory and effector T cells, based on their advanced maturation state. So, does Blimp-1 also impact later stages of T-cell differentiation? The new studies show it does – but not in the way one might have predicted. Blimp-1 regulates T-cell responses In their reports, the groups of Calame [1] and Nutt [2] used different tactics to circumvent the embryonic lethality associated with Blimp-1 deficiency (which is probably owing to vascular abnormalities resulting in inadequate placental development [8]). Martins et al. used a conditional knockout approach to limit Blimp-1 deletion to T cells [1], whereas Kallies and colleagues employed a gene knockin mutant, with the benefit that Blimp-1 transcription was reported by green fluorescent protein production, allowing the correlation of Blimp-1 expression with phenotypic or functional attributes [2]. Both groups found that Blimp-1-deficiency results in dramatic effects on T-cell homeostasis, manifesting as the accumulation of activated- and memory-phenotype T cells [1,2]. This correlates nicely with the finding of the two groups that Blimp-1 mRNA expression is low in naive Corresponding author: Jameson, S.C. ([email protected]). Available online 27 June 2006 www.sciencedirect.com
T cells, but elevated in memory and effector T cells (in both CD4 and CD8 subsets). Intriguingly, Blimp-1 is upregulated gradually following T-cell stimulation, requiring many days of activation or restimulation to induce maximal expression [1,2]. Given its function in B cells, we might expect Blimp-1 to curtail activated T-cell proliferation. Indeed, both groups find that in vitro-stimulated Blimp-1-deficient T cells expand better than wild-type cells. However, the basis for this effect is less clear. Martins et al. report enhanced proliferation of activated naive Blimp-1-deficient T cells [1], whereas Kallies et al. suggest that naive T-cell expansion is independent of Blimp-1 but that Blimp-1-deficient T cells accumulate following restimulation [2]. Furthermore, Kallies et al. demonstrate that this effect is owing to impaired activation-induced cell death, rather than enhanced proliferation [2]. Future studies must determine whether these differences relate to the Blimp-1deficient models used or simply the details of the in vitro culture systems employed. However, both reports indicate that Blimp-1 restrains the expansion of activated T cells. Kallies et al. also tested anti-viral T-cell responses in vivo, finding that Blimp-1-deficient cells showed normal initial responses but were slightly over-represented at later time points compared with normal T cells, perhaps implying more-efficient memory T-cell generation. Based on its role in plasma-cell differentiation, one might suppose that Blimp-1 would drive effector T-cell differentiation. By contrast, activated Blimp-1-deficient T cells produce more T-helper (Th)1 cytokines [interferon (IFN)-g and interleukin (IL)-2] [1,2]. This is, perhaps, not so unexpected because T-cell proliferation and effector differentiation often occur together, representing an important distinction from the obligatory withdrawal from the cell cycle of plasma cells. Indeed, elevated IL-2 production might explain the enhanced proliferation of Blimp-1deficient T cells stimulated at low density [1]. However, Blimp-1 loss did cause the defective production of IL-10 [1,2], a point discussed later. Together, these reports suggest that Blimp-1 limits T-cell responses. Following normal T-cell activation, Blimp-1 expression might dictate the end of the expansion phase. However, Blimp-1 could be more important in curtailing prolonged T-cell activation by driving cells into apoptosis instead of proliferation (Figure 1). Although this dampening effect might seem counterproductive, Blimp could be crucial for avoiding T-cell immunopathology, as discussed in the next section. Dangerous T cells fly without Blimp-1 The most dramatic effect of T-cell Blimp-1-deficiency is the spontaneous immunopathology reported by both groups
1471-4906/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2006.06.002
350
Update
TRENDS in Immunology Vol.27 No.8
Figure 1. A model for Blimp-1 regulation of T- and B-cell maturation. Blimp-1 expression levels in various subsets are indicated by the color intensity, with gray representing little or no Blimp-1 expression. In certain subsets (three-dimensional shapes), only certain cells might express Blimp-1. In B cells, Blimp-1 is essential for plasma-cell differentiation in primary and recall responses, and might drive the generation of certain memory B-cell subsets. In T cells, Blimp-1 expression increases gradually following activation, and Blimp-1 might restrain the generation of effector and memory populations by limiting proliferation and/or supporting AICD (activationinduced cell death). This might be of greatest importance in situations of prolonged activation, when Blimp-1 could limit the expansion of immunopathological T cells, either directly or indirectly (through Treg-cell populations).
[1,2]. Martins et al. observed progressive colitis, whereas Kallies et al. reported more-rapid and more-widespread lymphocytic infiltrations, correlating with lethal wasting disease. The divergent extent and severity of the disease might reflect the different approaches used, including a potential role for other Blimp-1-deficient hematopoietic cells in the system used by Nutt’s group [2]. Regardless, these data indicate that Blimp-1 is essential for restraining potentially hazardous T cells. How might Blimp-1 regulate colitis? The exuberant expansion of activated Blimp-1-deficient T cells might permit rare self-reactive T cells to become damaging. However, no current study of immunopathological diseases is complete without discussing regulatory T (Treg) cells. As mentioned, Blimp-1-deficient cells show impaired IL-10 production [1,2], an important cytokine for some forms of T-cell suppression [9,10]. Blimp-1 is found in some CD4+CD25+ T cells [1,2], and unpublished data from Rudensky’s lab has directly demonstrated Blimp-1 expression in the CD4+Foxp3+ Treg-cell subset (A. Rudensky, personal communication). However, in the Blimp-1 knockout systems, CD4+CD25+ and CD4+Foxp3+ T cells are generated, and are potent in vitro suppressors [1,2]. By contrast, the in vivo function of Blimp-1-deficient Treg cells is less clear: Kallies and colleagues report the normal function of these cells, whereas Martins et al. report severely impaired www.sciencedirect.com
suppressive activity [1,2]. These differences could relate to the specific colitis model investigated by the two groups (perhaps reflecting the relevance of IL-10 in the suppressive mechanism). Indeed, Calame’s team observe nearnormal suppression by Blimp-1-deficient Tregs when tested by in vivo assays similar to those used by the Nutt group (K. Calame, personal communication). Thus, these data suggest that certain, but not all, T-regulatory mechanisms could be compromised by Blimp-1-deficiency. Regardless of the basis for T-cell immunopathology, its occurrence might explain another discrepancy between the studies [1,2]. Martins et al. report that Blimp-1-deficiency causes the loss of immature CD4+CD8+ double-positive (DP) thymocytes, and suggest that Blimp-1 protects these cells from apoptosis [1]. However, as discussed previously [11], the spontaneous activation of Blimp-1-deficient T cells might offer an alternative explanation, because DP thymocytes are exquisitely susceptible to factors induced by activated T cells. Indeed, the Nutt group has observed reduced thymocyte cellularity with immunopathology progression (S. Nutt, personal communication). Hence, it is too early to tell if the loss of Blimp-1-deficient DP thymocytes is an autonomous effect. Does Blimp-1 regulate common target genes in B and T cells? Bcl-6 is an attractive candidate, because its repression is essential for plasma-cell generation [6] and Bcl-6
Update
TRENDS in Immunology
has been proposed to support memory T-cell generation [12]. However, although Calame’s group showed that Blimp-1-deficient effector-phenotype T cells upregulate Bcl-6, Nutt’s group did not observe this [1,2]. Given the narrow timing of Blimp-1 expression following T-cell stimulation, more-refined analysis might be required to answer this important question. These studies suggest intriguing parallels in the roles of Blimp-1 for B- and T-cell maturation, although, true to the nature of immunologists, the differences will, perhaps, prove even more interesting. Acknowledgements I thank Kathryn Calame, Stephen Nutt and Sasha Rudensky for providing insights and unpublished observations, and Kris Hogquist for critical input.
References 1 Martins, G.A. et al. (2006) Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol. 7, 457–465 2 Kallies, A. et al. (2006) Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat. Immunol. 7, 466–474
Vol.27 No.8
3 Turner, C.A., Jr et al. (1994) Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297–306 4 Kallies, A. et al. (2004) Plasma cell ontogeny defined by quantitative changes in Blimp-1 expression. J. Exp. Med. 200, 967–977 5 Shapiro-Shelef, M. et al. (2003) Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 6 Shapiro-Shelef, M. and Calame, K. (2005) Regulation of plasma-cell development. Nat. Rev. Immunol. 5, 230–242 7 Messika, E.J. et al. (1998) Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development. J. Exp. Med. 188, 515–525 8 Vincent, S.D. et al. (2005) The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells in the mouse. Development 132, 1315–1325 9 Annacker, O. et al. (2003) Interleukin-10 in the regulation of T cellinduced colitis. J. Autoimmun. 20, 277–279 10 von Boehmer, H. (2005) Mechanisms of suppression by suppressor T cells. Nat. Immunol. 6, 338–344 11 Fink, P.J. (2006) T cells join the Blimp-1 brigade. Nat. Immunol. 7, 445–446 12 Ichii, H. et al. (2002) Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells. Nat. Immunol. 3, 558–563
The Midwinter Conference of Immunologists 27-30 January 2007 Asilomar Conference Grounds, Pacific Grove (near Monterey), California, USA http://www.midwconfimmunol.org Chairs: Nilabh Shastri and Steven F. Ziegler This four-day conference will include sessions focusing on the transcriptional control of immunity, inflammatory responses in infection and allergy, inside-out signaling pathways for generating T-cell receptor ligands, the determination of cell fate in the immune system, and autoimmunity. Scheduled speakers include: Laurie H. Glimcher, Dan R. Littman, Sankar Ghosh, Jenny Ting, Stephen T. Smale, Richard M. Locksley, Anne O’Garra, Andrew D. Luster, Peter Cresswell, Mitchell Kronenberg, Sebastian Amigorena, Susan L. Swain, Douglas R. Green, Warren S. Pear, Kristin A. Hogquist, Jeffrey A. Bluestone, Maria-Grazia Roncarolo, Diane Mathis, Matthias von Herrath. The conference is limited to 650 attendees. The program and registration pack will be available in September from the Registrar: Ms Kim Gurney (e-mail: [email protected]). The registration deadline (without a late fee) is Monday 13 November 2006. After this date, contact the Registrar for available spaces.
www.sciencedirect.com
351