Lilin Ye’s group from Army Medical University revealed the novel mechanism in follicular regulatory T cell (TFR) differentiation
Source：Lilin Ye
2017-10-10
On Sep19th, 2017, Dr. Lilin Ye’s group from the Institute of Immunology, Third Military Medical University, reported in the journal Immunity about the mechanism in regulating Tfr differentiation (Xu et al., The kinase mTORC1 promotes the generation and suppressive function of follicular regulatory T cells. Immunity, 2017 Sep; 47(3):538-551).
Most of currently commerciallyavailable vaccines confer their protection efficacies by inducing high-affinity antibodies, which critically depend on the germinal center (GC) reaction. The GC reaction is initiated and amplified by the interaction between GC B cells and follicular helper T (Tfh) cells. These two populations act co-operatively to promote the generation of plasma cells and the production of high-affinity antibodies. However, prolonged and aberrant GC responses are implicated in both autoantibody-mediated autoimmune diseases and B-cell malignances. Thus, a GC reaction needs to be finely tuned.A unique subset of Foxp3+CD4+ regulatory T (Treg) cells, follicular regulatory T (Tfr) cells, specializes in repressing GC responses.Tfr cells differentiated from conventional Treg cells and limitexcessive GC reactions and maintain immune homeostasis primarily by suppressing Tfh and GC B cells in GC structure. Thus far, it still remains largely unknown regarding how Treg cells are driven to differentiate into Tfr cells.
Tfr differentiation is a multi-step and multifactor process. In the early stage of differentiation, cytokine receptors/co-stimulation mediated signals initiate the differentiation of Tfr cells from Treg cells. The coordination of these early molecular events likely induces the expression of transcription factors required forTfr differentiation, such as Bcl-6 and chemokine receptor CXCR5. CXCL13, a chemokine ligand specific to CXCR5, attracts Tfr cellsmoving towards germinal center through CXCL13-CXCR5 axis. In addition, Tfr cells upregulates the SLAM-associated protein (SAP) expression, which in turn mediates the close interaction between Tfr cells and GC B cells in B-cell follicles. Nonetheless, how these various signals are integrated to instruct the differentiation of Tfr cells from Treg cellsis still not clear in the field.
In this project, the researchers focused on the mechanistic target of rapamycin (mTOR), which is an evolutionarily conserved serine/threonine kinase. The mTOR kinase can form two functionally and structurally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Both complexes control various cellular processes, including cell growth, proliferation and survival, by sensing and integrating environmental cues.These two kinase complexes regulate a wide variety of T-cell immune responses, including Th1, Th17, Treg and memory CD8 T cells. The differentiation of Tfr cells involves a very comprehensive and complex immune microenvironment: itbeginsin T-cell zone of lymphoid organs, followed by migrating towards B-cell follicle and then moving to germinal center to exert their suppressive function. Whether and how the mTOR family would integrate environmental cueso regulate Tfr differentiation is of great interest.
Herein they found that mTORC1 but not mTORC2 activity is preferentially enhanced in Tfr cells compared with Treg, Tfh and Th1 cells following viral infection or protein immunization. By transiently treating Treg precursors with rapamycin, a pharmacological inhibitor of mTORC1 signaling, for 4 hours, they found that both the proportion and number of Foxp3+CXCR5+ Tfr cells were substantially decreased in the rapamycin-treated Treg group compared with the vehicle-treated Treg group. Furthermore, the conditionally deletion of only a single copy of Rptor alleles in Foxp3+ Treg cells did not apparently impact the proliferation and function of Treg cells, however, this greatly impaired the Treg-to-Tfr transition. Mechanistically, mTORC1-mediated phosphorylation of the transcription factor STAT3 promoted the expression of the transcription factor TCF-1. Subsequently, TCF-1 bound to the Bcl6 promoter to initiate Bcl6 expression, which then launched the Tfr cell differentiation program.
In summary, they have demonstrated the critical mechanism during the Treg to Tfr differentiation, which may provide novel insights into improving protective immunity or treating autoimmune diseases.
Most of currently commerciallyavailable vaccines confer their protection efficacies by inducing high-affinity antibodies, which critically depend on the germinal center (GC) reaction. The GC reaction is initiated and amplified by the interaction between GC B cells and follicular helper T (Tfh) cells. These two populations act co-operatively to promote the generation of plasma cells and the production of high-affinity antibodies. However, prolonged and aberrant GC responses are implicated in both autoantibody-mediated autoimmune diseases and B-cell malignances. Thus, a GC reaction needs to be finely tuned.A unique subset of Foxp3+CD4+ regulatory T (Treg) cells, follicular regulatory T (Tfr) cells, specializes in repressing GC responses.Tfr cells differentiated from conventional Treg cells and limitexcessive GC reactions and maintain immune homeostasis primarily by suppressing Tfh and GC B cells in GC structure. Thus far, it still remains largely unknown regarding how Treg cells are driven to differentiate into Tfr cells.
Tfr differentiation is a multi-step and multifactor process. In the early stage of differentiation, cytokine receptors/co-stimulation mediated signals initiate the differentiation of Tfr cells from Treg cells. The coordination of these early molecular events likely induces the expression of transcription factors required forTfr differentiation, such as Bcl-6 and chemokine receptor CXCR5. CXCL13, a chemokine ligand specific to CXCR5, attracts Tfr cellsmoving towards germinal center through CXCL13-CXCR5 axis. In addition, Tfr cells upregulates the SLAM-associated protein (SAP) expression, which in turn mediates the close interaction between Tfr cells and GC B cells in B-cell follicles. Nonetheless, how these various signals are integrated to instruct the differentiation of Tfr cells from Treg cellsis still not clear in the field.
In this project, the researchers focused on the mechanistic target of rapamycin (mTOR), which is an evolutionarily conserved serine/threonine kinase. The mTOR kinase can form two functionally and structurally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Both complexes control various cellular processes, including cell growth, proliferation and survival, by sensing and integrating environmental cues.These two kinase complexes regulate a wide variety of T-cell immune responses, including Th1, Th17, Treg and memory CD8 T cells. The differentiation of Tfr cells involves a very comprehensive and complex immune microenvironment: itbeginsin T-cell zone of lymphoid organs, followed by migrating towards B-cell follicle and then moving to germinal center to exert their suppressive function. Whether and how the mTOR family would integrate environmental cueso regulate Tfr differentiation is of great interest.
Herein they found that mTORC1 but not mTORC2 activity is preferentially enhanced in Tfr cells compared with Treg, Tfh and Th1 cells following viral infection or protein immunization. By transiently treating Treg precursors with rapamycin, a pharmacological inhibitor of mTORC1 signaling, for 4 hours, they found that both the proportion and number of Foxp3+CXCR5+ Tfr cells were substantially decreased in the rapamycin-treated Treg group compared with the vehicle-treated Treg group. Furthermore, the conditionally deletion of only a single copy of Rptor alleles in Foxp3+ Treg cells did not apparently impact the proliferation and function of Treg cells, however, this greatly impaired the Treg-to-Tfr transition. Mechanistically, mTORC1-mediated phosphorylation of the transcription factor STAT3 promoted the expression of the transcription factor TCF-1. Subsequently, TCF-1 bound to the Bcl6 promoter to initiate Bcl6 expression, which then launched the Tfr cell differentiation program.
In summary, they have demonstrated the critical mechanism during the Treg to Tfr differentiation, which may provide novel insights into improving protective immunity or treating autoimmune diseases.
