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B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1

Karnowski, Alex, Chevrier, Stephane, Belz, Gabrielle T., Mount, Adele, Emslie, Dianne, D’Costa, Kathy, Tarlinton, David M., Kallies, Axel, Corcoran, Lynn M.·2012·Journal of Experimental Medicine
DOI 10.1084/jem.20111504PMC PMC3478936
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Abstract

A strong humoral response to infection requires the collaboration of several hematopoietic cell types that communicate via antigen presentation, surface coreceptors and their ligands, and secreted factors. The proinflammatory cytokine IL-6 has been shown to promote the differentiation of activated CD4+ T cells into T follicular helper cells (TFH cells) during an immune response. TFH cells collaborate with B cells in the formation of germinal centers (GCs) during T cell–dependent antibody responses, in part through secretion of critical cytokines such as IL-21. In this study, we demonstrate that loss of either IL-6 or IL-21 has marginal effects on the generation of TFH cells and on the formation of GCs during the response to acute viral infection. However, mice lacking both IL-6 and IL-21 were unable to generate a robust TFH cell–dependent immune response. We found that IL-6 production in follicular B cells in the draining lymph node was an important early event during the antiviral response and that B cell–derived IL-6 was necessary and sufficient to induce IL-21 from CD4+ T cells in vitro and to support TFH cell development in vivo. Finally, the transcriptional activator Oct2 and its cofactor OBF-1 were identified as regulators of Il6 expression in B cells.

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Figures

Figure 1. Combined loss of IL-6 and IL-21 compromises GC formation in influenza infection. Analysis of GC B cells in C57BL/6 (WT), IL-6, IL-21, and IL-6/IL-21 double-deficient mice (DKO). Mice were analyzed on day 10 after influenza infection. Results shown are from three to six independent experiments, totaling 4 naive WT and 21 WT, 8 Il6−/−, 8 Il21−/−, and 16 DKO-infected mice, respectively. (A) Cells from the draining mLNs and from the spleen were stained for GC B cells with α-B220, α-Fas, and PNA, and the percentage of B220+ cells that were also PNA+/Fas+ is shown. (B and C) Frequency distribution of GC B cells in spleens and mLNs from WT and mutant mice analyzed on day 10 of infection. (D) Ratio of GC area to B cell follicle area in spleens of WT and DKO animals on day 10, as measured from histological sections. Each symbol represents an individual animal. (E and F) Frequency distribution of GC B cells from WT and mutant mice analyzed on day 21 of infection. Each symbol represents an individual animal. Statistical analyses used Tukey’s multiple comparison tests. ***, P < 0.001; **, P = 0.001–0.001; *, P = 0.01–0.05. Bars and numbers show mean percentage with ± SEM. Results are from three to six independent experiments. (G) Representative histological staining to detect GCs in spleens from control or mutant mice 10 d after influenza infection. Paraffin sections were stained with α-GL7, α-B220, and α-CD3. Bars, 50 µm.
Figure 1. Combined loss of IL-6 and IL-21 compromises GC formation in influenza infection. Analysis of GC B cells in C57BL/6 (WT), IL-6, IL-21, and IL-6/IL-21 double-deficient mice (DKO). Mice were analyzed on day 10 after influenza infection. Results shown are from three to six independent experiments, totaling 4 naive WT and 21 WT, 8 Il6−/−, 8 Il21−/−, and 16 DKO-infected mice, respectively. (A) Cells from the draining mLNs and from the spleen were stained for GC B cells with α-B220, α-Fas, and PNA, and the percentage of B220+ cells that were also PNA+/Fas+ is shown. (B and C) Frequency distribution of GC B cells in spleens and mLNs from WT and mutant mice analyzed on day 10 of infection. (D) Ratio of GC area to B cell follicle area in spleens of WT and DKO animals on day 10, as measured from histological sections. Each symbol represents an individual animal. (E and F) Frequency distribution of GC B cells from WT and mutant mice analyzed on day 21 of infection. Each symbol represents an individual animal. Statistical analyses used Tukey’s multiple comparison tests. ***, P < 0.001; **, P = 0.001–0.001; *, P = 0.01–0.05. Bars and numbers show mean percentage with ± SEM. Results are from three to six independent experiments. (G) Representative histological staining to detect GCs in spleens from control or mutant mice 10 d after influenza infection. Paraffin sections were stained with α-GL7, α-B220, and α-CD3. Bars, 50 µm.CC BY-NC-SA · PubMed Central
Figure 2. Combined loss of IL-6 and IL-21 does not affect the virus-specific CD8 response but limits TFH formation and the antibody response in influenza infection. Analysis of anti-influenza CD8 responses in WT and DKO animals. Mice were analyzed on day 10 after infection. (A) Splenocytes and cells from the bronchoalveolar lavage (BAL) were stained with α-CD8, α-CD44, and either NP-tetramer or PA-tetramer. Frequency distribution of splenic, virus-specific CD8+ T cells (tetramer stains: NP, black symbols; PA, gray symbols) is shown in a representative of two independent experiments using three to five animals of each genotype. (B) Frequency distribution of KLRG1/CD44 double-positive CD8+ T cells in spleen and bronchoalveolar lavage. Each symbol represents an individual animal. Bars and numbers show mean percentage with ± SEM. (C) WT, IL-6– or IL-21–deficient, and DKO mice were infected with HKx31 influenza virus and analyzed on day 10 after infection. Cells from the mLNs were stained for TFH cells with α-CD4, α-CXCR5, and α–PD-1, and the percentage of PD-1/CXCR5 double-positive CD4+ T cells was measured. (D) Frequency of TFH from WT and mutant mice analyzed on day 10 after infection. Representative example shown of two to six independent experiments, totaling 6 naive WT, 23 WT, 8 Il6−/−, 8 Il21−/−, and 19 DKO-infected mice, respectively. (E) CD4+PD-1+CXCR5+ TFH cells and CD4+PD-1−CXCR5− T cells were sorted from spleen on day 14 of HKx31 influenza infection. Bcl6 and Il21 expression was measured by RT-qPCR. (As expected, Il21 is not expressed in the DKO mice. This is a control only.) Bars and numbers show relative gene expression normalized to the housekeeping gene, Hmbs, ± SEM (n = 3). (F) IL-21–GFP reporter mice, on a WT or Il6−/− background, were infected, and mLNs were harvested on days 6, 8, and 10 and stained for TFH cells (CD4, TCR-β, CXCR5, and PD-1). The dot plot shows IL-21–expressing cells in the CD4+/TCR-β+ gate on day 10. (G) Time course showing total numbers of IL-21–expressing TFH in the draining mLNs from days 6 to 10 of infection. Numbers show means ± SEM of five animals in each group. IL-21/GFP+ cells were also CD4+, TCR-β+, PD-1+, CXCR5+. (H) IgM and IgG HKx31-specific responses in WT, IL-6, IL-21R, and DKO mice. Serum IgM and IgG titers were measured by ELISA on day 14 of the influenza infection and are represented as the reciprocal of serum dilutions, giving an absorbance that was 50% of maximum value for the assay. Each symbol represents an individual animal. ***, P < 0.001; **, P = 0.001–0.001; *, P = 0.01–0.05. Bars and numbers show mean dilution ± SEM.
Figure 2. Combined loss of IL-6 and IL-21 does not affect the virus-specific CD8 response but limits TFH formation and the antibody response in influenza infection. Analysis of anti-influenza CD8 responses in WT and DKO animals. Mice were analyzed on day 10 after infection. (A) Splenocytes and cells from the bronchoalveolar lavage (BAL) were stained with α-CD8, α-CD44, and either NP-tetramer or PA-tetramer. Frequency distribution of splenic, virus-specific CD8+ T cells (tetramer stains: NP, black symbols; PA, gray symbols) is shown in a representative of two independent experiments using three to five animals of each genotype. (B) Frequency distribution of KLRG1/CD44 double-positive CD8+ T cells in spleen and bronchoalveolar lavage. Each symbol represents an individual animal. Bars and numbers show mean percentage with ± SEM. (C) WT, IL-6– or IL-21–deficient, and DKO mice were infected with HKx31 influenza virus and analyzed on day 10 after infection. Cells from the mLNs were stained for TFH cells with α-CD4, α-CXCR5, and α–PD-1, and the percentage of PD-1/CXCR5 double-positive CD4+ T cells was measured. (D) Frequency of TFH from WT and mutant mice analyzed on day 10 after infection. Representative example shown of two to six independent experiments, totaling 6 naive WT, 23 WT, 8 Il6−/−, 8 Il21−/−, and 19 DKO-infected mice, respectively. (E) CD4+PD-1+CXCR5+ TFH cells and CD4+PD-1−CXCR5− T cells were sorted from spleen on day 14 of HKx31 influenza infection. Bcl6 and Il21 expression was measured by RT-qPCR. (As expected, Il21 is not expressed in the DKO mice. This is a control only.) Bars and numbers show relative gene expression normalized to the housekeeping gene, Hmbs, ± SEM (n = 3). (F) IL-21–GFP reporter mice, on a WT or Il6−/− background, were infected, and mLNs were harvested on days 6, 8, and 10 and stained for TFH cells (CD4, TCR-β, CXCR5, and PD-1). The dot plot shows IL-21–expressing cells in the CD4+/TCR-β+ gate on day 10. (G) Time course showing total numbers of IL-21–expressing TFH in the draining mLNs from days 6 to 10 of infection. Numbers show means ± SEM of five animals in each group. IL-21/GFP+ cells were also CD4+, TCR-β+, PD-1+, CXCR5+. (H) IgM and IgG HKx31-specific responses in WT, IL-6, IL-21R, and DKO mice. Serum IgM and IgG titers were measured by ELISA on day 14 of the influenza infection and are represented as the reciprocal of serum dilutions, giving an absorbance that was 50% of maximum value for the assay. Each symbol represents an individual animal. ***, P < 0.001; **, P = 0.001–0.001; *, P = 0.01–0.05. Bars and numbers show mean dilution ± SEM.CC BY-NC-SA · PubMed Central
Figure 3. IL-6 and IL-21 are expressed early during an influenza infection. (A) CD4+ and CD19+ cells were isolated from mLNs on the indicated days after influenza infection. Il21 or Il6 mRNA expression was measured by qPCR. (B) Cells from the mLNs of naive and infected animals were stained with α-CD19, α-CD11c, α-CD11b, α-CD69, and α-CD86. Resting (G1) and activated follicular B cells (G2) were sorted. Bars and numbers show relative Il6 expression normalized to Hmbs ± SEM (n = 3) in each sorted population. (C) Time course of total cell numbers of activated and GC B cells, DCs, and macrophages in mLNs of infected mice. Numbers are means ± SEM of five mice. (D) Co-culture of WT naive CD62L+/CD4+ T cells, stimulated with α-CD3/α-CD28, and different numbers of CpG-preactivated B cells from control or IL-6–deficient mice. The left panel shows CD3/CD28-activated T cells with medium alone or with recombinant IL-6. After 4 d of co-culture, the CD4+ T cells were sorted, and Il21 mRNA expression was determined. The results are representative of three independent experiments. (A and D) Error bars represent SDs of triplicate assays. (E and F) WT, congenic Ly5.1+ B cells were injected into WT and DKO animals 2 d before influenza infection. 10 d after infection, cells from the mLNs were stained for TFH and GC B cells as described for Figs. 2 C and 1 A, respectively. Figures show fold change of each animal’s TFH or GC B cells compared with the mean percentage of TFH or GC B cells from controls within each experiment. Results are from three to six independent experiments. (E) TFH ratio comparing WT and DKO animals without or with rescue by WT Ly5.1 B cells. (F) GC B cell ratio comparing WT and DKO animals without or with rescue by WT Ly5.1 B cells. Each symbol represents an individual animal. Statistical analyses were performed using the two-sample Wilcoxon test, and all p-values are two-sided. Bars and numbers show fold change ± SEM.
Figure 3. IL-6 and IL-21 are expressed early during an influenza infection. (A) CD4+ and CD19+ cells were isolated from mLNs on the indicated days after influenza infection. Il21 or Il6 mRNA expression was measured by qPCR. (B) Cells from the mLNs of naive and infected animals were stained with α-CD19, α-CD11c, α-CD11b, α-CD69, and α-CD86. Resting (G1) and activated follicular B cells (G2) were sorted. Bars and numbers show relative Il6 expression normalized to Hmbs ± SEM (n = 3) in each sorted population. (C) Time course of total cell numbers of activated and GC B cells, DCs, and macrophages in mLNs of infected mice. Numbers are means ± SEM of five mice. (D) Co-culture of WT naive CD62L+/CD4+ T cells, stimulated with α-CD3/α-CD28, and different numbers of CpG-preactivated B cells from control or IL-6–deficient mice. The left panel shows CD3/CD28-activated T cells with medium alone or with recombinant IL-6. After 4 d of co-culture, the CD4+ T cells were sorted, and Il21 mRNA expression was determined. The results are representative of three independent experiments. (A and D) Error bars represent SDs of triplicate assays. (E and F) WT, congenic Ly5.1+ B cells were injected into WT and DKO animals 2 d before influenza infection. 10 d after infection, cells from the mLNs were stained for TFH and GC B cells as described for Figs. 2 C and 1 A, respectively. Figures show fold change of each animal’s TFH or GC B cells compared with the mean percentage of TFH or GC B cells from controls within each experiment. Results are from three to six independent experiments. (E) TFH ratio comparing WT and DKO animals without or with rescue by WT Ly5.1 B cells. (F) GC B cell ratio comparing WT and DKO animals without or with rescue by WT Ly5.1 B cells. Each symbol represents an individual animal. Statistical analyses were performed using the two-sample Wilcoxon test, and all p-values are two-sided. Bars and numbers show fold change ± SEM.CC BY-NC-SA · PubMed Central
Figure 4. Induction of IL-6 in activated B cells is dependent on Oct2 and OBF-1. (A and B) qPCR measurement of Il6 expression in sorted and LPS- or CpG-stimulated Gr1+, Mac1+ macrophages or BM-derived DCs from WT or Obf-1−/− mice. (C) Western blot analysis of Oct2 and OBF-1 in mature resting or CpG- or LPS-stimulated B cells. Blots were probed with α–OBF-1, α-Oct2, or α-actin. (D and E) Il6 expression in sorted and activated splenic B220+ B cells from OBF-1–deficient or WT mice and Oct+/+ or Oct−/− B cells from fetal liver reconstituted mice. Bars and numbers show relative gene expression normalized to Hmbs expression ± SEM (n = 3). (F) In vitro generation of IL-21–producing cells. Co-culture of WT naive CD4+, CD62L+ T cells, activated with α-CD3/α-CD28, with different numbers of CpG-preactivated B cells from WT, Obf-1−/−, Oct2−/−, or IL-6–deficient mice. After 4 d of co-culture, the CD4+ T cells were sorted, and Il21 expression was determined by qPCR. (A and F) Error bars represent SDs of triplicate assays. (G) T cells stimulated with medium alone, with recombinant IL-6, or with B cells and recombinant IL-6. Il21 expression was determined by qPCR and normalized as described for D–E. Bars and numbers show relative gene expression normalized to Hmbs expression ± SEM (n = 3).
Figure 4. Induction of IL-6 in activated B cells is dependent on Oct2 and OBF-1. (A and B) qPCR measurement of Il6 expression in sorted and LPS- or CpG-stimulated Gr1+, Mac1+ macrophages or BM-derived DCs from WT or Obf-1−/− mice. (C) Western blot analysis of Oct2 and OBF-1 in mature resting or CpG- or LPS-stimulated B cells. Blots were probed with α–OBF-1, α-Oct2, or α-actin. (D and E) Il6 expression in sorted and activated splenic B220+ B cells from OBF-1–deficient or WT mice and Oct+/+ or Oct−/− B cells from fetal liver reconstituted mice. Bars and numbers show relative gene expression normalized to Hmbs expression ± SEM (n = 3). (F) In vitro generation of IL-21–producing cells. Co-culture of WT naive CD4+, CD62L+ T cells, activated with α-CD3/α-CD28, with different numbers of CpG-preactivated B cells from WT, Obf-1−/−, Oct2−/−, or IL-6–deficient mice. After 4 d of co-culture, the CD4+ T cells were sorted, and Il21 expression was determined by qPCR. (A and F) Error bars represent SDs of triplicate assays. (G) T cells stimulated with medium alone, with recombinant IL-6, or with B cells and recombinant IL-6. Il21 expression was determined by qPCR and normalized as described for D–E. Bars and numbers show relative gene expression normalized to Hmbs expression ± SEM (n = 3).CC BY-NC-SA · PubMed Central
Figure 5. Functional octamer factor binding sites in the Il6 locus. (A) Organization of the Il6 locus and location of the core promoter region. Positions of four consensus octamer sites identified in silico are shown. AK039125 is an adjacent gene. (B) EMSA analysis on nuclear extracts from 24-h CpG-stimulated splenic B cells, performed using short fragments (160–207 bp) containing the consensus octamer site (ATGCAAT) from an Ig heavy chain promoter or octamer sequences identified in the Il6 locus (site 1, ATTTGCAT −3302; site 2, TTTTGCAT −1438; site 3, ATTTGCAT 3793; site 4, ATTTGCAT 10615). Specific complex formation was detected through supershifts using α-Oct2 or α–OBF-1 monoclonal antibodies, as indicated. Oct2–DNA complexes are indicated with asterisks. The results are representative of three independent experiments. (C and D) Immunoprecipitation (ChIP) of chromatin from purified splenic B cells from mice of the indicated genotypes, using preimmune and hyperimmune rabbit serum specific for Oct2. (C) Cd36 is a known Oct2 target gene (König et al., 1995). (D) ChIP on the same chromatin as in C, but examining the octamer-containing Il6 gene sequences identified in A and positive by EMSA (B). Values in all graphs are means ± SEM (n = 3).
Figure 5. Functional octamer factor binding sites in the Il6 locus. (A) Organization of the Il6 locus and location of the core promoter region. Positions of four consensus octamer sites identified in silico are shown. AK039125 is an adjacent gene. (B) EMSA analysis on nuclear extracts from 24-h CpG-stimulated splenic B cells, performed using short fragments (160–207 bp) containing the consensus octamer site (ATGCAAT) from an Ig heavy chain promoter or octamer sequences identified in the Il6 locus (site 1, ATTTGCAT −3302; site 2, TTTTGCAT −1438; site 3, ATTTGCAT 3793; site 4, ATTTGCAT 10615). Specific complex formation was detected through supershifts using α-Oct2 or α–OBF-1 monoclonal antibodies, as indicated. Oct2–DNA complexes are indicated with asterisks. The results are representative of three independent experiments. (C and D) Immunoprecipitation (ChIP) of chromatin from purified splenic B cells from mice of the indicated genotypes, using preimmune and hyperimmune rabbit serum specific for Oct2. (C) Cd36 is a known Oct2 target gene (König et al., 1995). (D) ChIP on the same chromatin as in C, but examining the octamer-containing Il6 gene sequences identified in A and positive by EMSA (B). Values in all graphs are means ± SEM (n = 3).CC BY-NC-SA · PubMed Central
Figure 6. Loss of OBF-1 but not Oct2 results in loss of GCs and reduction of TFH during influenza infection. Analysis of GC B cells and TFH cells in control or OBF-1– or Oct2-deficient mice on day 10 of infection. (A and B) mLN cells were stained with α-B220, α-Fas, and PNA to detect GC B cells. Representative staining is shown in A, and summary of data for all mice is shown in B. (C and D) mLN cells were stained with α-CD4, α-CXCR5, and α–PD-1 to detect TFH cells. Representative staining is shown in C, and the frequency distribution for all mice is shown in D. (E) Analysis of Bcl6 and Il21 expression in CD4+, PD-1+, and CXCR5+ TFH sorted from spleens of WT and Obf-1−/− mice 10 d after influenza infection. Bars and numbers show mean normalized gene expression with ± SEM (n = 3). (F and G) TFH and GC B cells were analyzed in WT:CD19−/−, Obf-1−/−:CD19−/−, WT:TCRα−/−, and Obf-1−/−:TCRα−/− mixed BM chimeras 10 d after influenza infection. (F) Cells from the mLNs were stained for GC B cells as described in A and B. (G) Cells from the mLNs were stained for TFH cells, as described for E. Each symbol represents an individual animal. ***, P < 0.001; *, P = 0.01–0.05. Results are from three independent experiments.
Figure 6. Loss of OBF-1 but not Oct2 results in loss of GCs and reduction of TFH during influenza infection. Analysis of GC B cells and TFH cells in control or OBF-1– or Oct2-deficient mice on day 10 of infection. (A and B) mLN cells were stained with α-B220, α-Fas, and PNA to detect GC B cells. Representative staining is shown in A, and summary of data for all mice is shown in B. (C and D) mLN cells were stained with α-CD4, α-CXCR5, and α–PD-1 to detect TFH cells. Representative staining is shown in C, and the frequency distribution for all mice is shown in D. (E) Analysis of Bcl6 and Il21 expression in CD4+, PD-1+, and CXCR5+ TFH sorted from spleens of WT and Obf-1−/− mice 10 d after influenza infection. Bars and numbers show mean normalized gene expression with ± SEM (n = 3). (F and G) TFH and GC B cells were analyzed in WT:CD19−/−, Obf-1−/−:CD19−/−, WT:TCRα−/−, and Obf-1−/−:TCRα−/− mixed BM chimeras 10 d after influenza infection. (F) Cells from the mLNs were stained for GC B cells as described in A and B. (G) Cells from the mLNs were stained for TFH cells, as described for E. Each symbol represents an individual animal. ***, P < 0.001; *, P = 0.01–0.05. Results are from three independent experiments.CC BY-NC-SA · PubMed Central

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Show all 5 references

Research works printed but not linked: 84

  1. Ansel, 1999, In vivo–activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines, J. Exp. Med., 190, 1123, 10.1084/jem.190.8.1123 · DOI
  2. Arguni, 2006, JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells, Int. Immunol., 18, 1079, 10.1093/intimm/dxl041 · DOI
  3. Baccam, 2003, CD40-mediated transcriptional regulation of the IL-6 gene in B lymphocytes: involvement of NF-kappa B, AP-1, and C/EBP, J. Immunol., 170, 3099, 10.4049/jimmunol.170.6.3099 · DOI
  4. Bartholdy, 2006, The Ets factor Spi-B is a direct critical target of the coactivator OBF-1, Proc. Natl. Acad. Sci. USA., 103, 11665, 10.1073/pnas.0509430103 · DOI
  5. Batten, 2010, IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells, J. Exp. Med., 207, 2895, 10.1084/jem.20100064 · DOI
  6. Baumjohann, 2011, Cutting Edge: Distinct waves of BCL6 expression during T follicular helper cell development, J. Immunol., 187, 2089, 10.4049/jimmunol.1101393 · DOI
  7. Belz, 2000, Contemporary analysis of MHC-related immunodominance hierarchies in the CD8+ T cell response to influenza A viruses, J. Immunol., 165, 2404, 10.4049/jimmunol.165.5.2404 · DOI
  8. Bessa, 2010, Cutting edge: IL-21 and TLR signaling regulate germinal center responses in a B cell-intrinsic manner, J. Immunol., 184, 4615, 10.4049/jimmunol.0903949 · DOI
  9. Blink, 2005, Early appearance of germinal center–derived memory B cells and plasma cells in blood after primary immunization, J. Exp. Med., 201, 545, 10.1084/jem.20042060 · DOI
  10. Brocker, 1999, CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells by OX40-ligand expressed on dendritic cells leads to the accumulation of CD4 T cells in B follicles, Eur. J. Immunol., 29, 1610, 10.1002/(SICI)1521-4141(199905)29:05<1610::AID-IMMU1610>3.0.CO;2-8 · DOI
  11. Brunner, 2007, BOB.1/OBF.1 controls the balance of TH1 and TH2 immune responses, EMBO J., 26, 3191, 10.1038/sj.emboj.7601742 · DOI
  12. Cannons, 2010, Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84, Immunity., 32, 253, 10.1016/j.immuni.2010.01.010 · DOI
  13. Casey, 2007, IL-21 promotes differentiation of naive CD8 T cells to a unique effector phenotype, J. Immunol., 178, 7640, 10.4049/jimmunol.178.12.7640 · DOI
  14. Cepek, 1996, Sequence-specific DNA binding of the B-cell-specific coactivator OCA-B, Genes Dev., 10, 2079, 10.1101/gad.10.16.2079 · DOI
  15. Choi, 2011, ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6, Immunity., 34, 932, 10.1016/j.immuni.2011.03.023 · DOI
  16. Corcoran, 1994, Oct-2 is required early in T cell-independent B cell activation for G1 progression and for proliferation, Immunity., 1, 635, 10.1016/1074-7613(94)90035-3 · DOI
  17. Corcoran, 1993, Oct-2, although not required for early B-cell development, is critical for later B-cell maturation and for postnatal survival, Genes Dev., 7, 570, 10.1101/gad.7.4.570 · DOI
  18. Corcoran, 2004, All known in vivo functions of the Oct-2 transcription factor require the C-terminal protein domain, J. Immunol., 172, 2962, 10.4049/jimmunol.172.5.2962 · DOI
  19. Corcoran, 2005, Differential requirement for OBF-1 during antibody-secreting cell differentiation, J. Exp. Med., 201, 1385, 10.1084/jem.20042325 · DOI
  20. Crotty, 2011, Follicular helper CD4 T cells (TFH), Annu. Rev. Immunol., 29, 621, 10.1146/annurev-immunol-031210-101400 · DOI · Paper page
  21. Cucak, 2009, Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells, Immunity., 31, 491, 10.1016/j.immuni.2009.07.005 · DOI
  22. Deenick, 2010, Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling, Immunity., 33, 241, 10.1016/j.immuni.2010.07.015 · DOI
  23. Deenick, 2011, Regulation of T follicular helper cell formation and function by antigen presenting cells, Curr. Opin. Immunol., 23, 111, 10.1016/j.coi.2010.10.007 · DOI
  24. Dienz, 2009, The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells, J. Exp. Med., 206, 69, 10.1084/jem.20081571 · DOI
  25. Eddahri, 2009, Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities, Blood., 113, 2426, 10.1182/blood-2008-04-154682 · DOI
  26. Emslie, 2008, Oct2 enhances antibody-secreting cell differentiation through regulation of IL-5 receptor α chain expression on activated B cells, J. Exp. Med., 205, 409, 10.1084/jem.20072049 · DOI
  27. Engel, 1995, Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule, Immunity., 3, 39, 10.1016/1074-7613(95)90157-4 · DOI
  28. Eto, 2011, IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation, PLoS ONE., 6, e17739, 10.1371/journal.pone.0017739 · DOI
  29. Fazilleau, 2009, Follicular helper T cells: lineage and location, Immunity., 30, 324, 10.1016/j.immuni.2009.03.003 · DOI
  30. Flynn, 1998, Virus-specific CD8+ T cells in primary and secondary influenza pneumonia, Immunity., 8, 683, 10.1016/S1074-7613(00)80573-7 · DOI
  31. Garside, 1998, Visualization of specific B and T lymphocyte interactions in the lymph node, Science., 281, 96, 10.1126/science.281.5373.96 · DOI
  32. Goenka, 2011, Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultimate effector differentiation, J. Immunol., 187, 1091, 10.4049/jimmunol.1100853 · DOI
  33. Gstaiger, 1996, The B cell coactivator Bob1 shows DNA sequence-dependent complex formation with Oct-1/Oct-2 factors, leading to differential promoter activation, EMBO J., 15, 2781, 10.1002/j.1460-2075.1996.tb00638.x · DOI
  34. Harker, 2011, Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection, Science., 334, 825, 10.1126/science.1208421 · DOI · Paper page
  35. Haynes, 2007, Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation, J. Immunol., 179, 5099, 10.4049/jimmunol.179.8.5099 · DOI
  36. Johnston, 2009, Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation, Science., 325, 1006, 10.1126/science.1175870 · DOI · Paper page
  37. Kerfoot, 2011, Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone, Immunity., 34, 947, 10.1016/j.immuni.2011.03.024 · DOI
  38. Kim, 1996, The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for normal production of immunoglobulin isotypes, Nature., 383, 542, 10.1038/383542a0 · DOI
  39. King, 2009, New insights into the differentiation and function of T follicular helper cells, Nat. Rev. Immunol., 9, 757, 10.1038/nri2644 · DOI
  40. King, 2008, T follicular helper (TFH) cells in normal and dysregulated immune responses, Annu. Rev. Immunol., 26, 741, 10.1146/annurev.immunol.26.021607.090344 · DOI
  41. Kitano, 2011, Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity, Immunity., 34, 961, 10.1016/j.immuni.2011.03.025 · DOI
  42. König, 1995, Identification of CD36 as the first gene dependent on the B-cell differentiation factor Oct-2, Genes Dev., 9, 1598, 10.1101/gad.9.13.1598 · DOI
  43. Kopf, 1998, Interleukin 6 influences germinal center development and antibody production via a contribution of C3 complement component, J. Exp. Med., 188, 1895, 10.1084/jem.188.10.1895 · DOI
  44. Kwon, 2009, Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors, Immunity., 31, 941, 10.1016/j.immuni.2009.10.008 · DOI
  45. Lins, 2003, OBF1 enhances transcriptional potential of Oct1, EMBO J., 22, 2188, 10.1093/emboj/cdg199 · DOI
  46. Linterman, 2010, IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses, J. Exp. Med., 207, 353, 10.1084/jem.20091738 · DOI
  47. Lüthje, 2012, The development and fate of follicular helper T cells defined by an IL-21 reporter mouse, Nat. Immunol., 13, 491, 10.1038/ni.2261 · DOI
  48. Ma, 2009, Early commitment of naïve human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12, Immunol. Cell Biol., 87, 590, 10.1038/icb.2009.64 · DOI
  49. Messeguer, 2002, PROMO: detection of known transcription regulatory elements using species-tailored searches, Bioinformatics., 18, 333, 10.1093/bioinformatics/18.2.333 · DOI
  50. Naik, 2005, Development of murine plasmacytoid dendritic cell subsets, Immunol. Cell Biol., 83, 563, 10.1111/j.1440-1711.2005.01390.x · DOI
  51. Novy, 2011, Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection, J. Immunol., 186, 2729, 10.4049/jimmunol.1003009 · DOI
  52. Nurieva, 2008, Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages, Immunity., 29, 138, 10.1016/j.immuni.2008.05.009 · DOI · Paper page
  53. Nutt, 2011, Germinal center B and follicular helper T cells: siblings, cousins or just good friends?, Nat. Immunol., 12, 472, 10.1038/ni.2019 · DOI
  54. Ozaki, 2004, Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6, J. Immunol., 173, 5361, 10.4049/jimmunol.173.9.5361 · DOI · Paper page
  55. Parrish-Novak, 2000, Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function, Nature., 408, 57, 10.1038/35040504 · DOI
  56. Philpott, 1992, Lymphoid development in mice congenitally lacking T cell receptor alpha beta-expressing cells, Science., 256, 1448, 10.1126/science.1604321 · DOI
  57. Poholek, 2010, In vivo regulation of Bcl6 and T follicular helper cell development, J. Immunol., 185, 313, 10.4049/jimmunol.0904023 · DOI
  58. Qin, 1998, OCA-B integrates B cell antigen receptor-, CD40L- and IL 4-mediated signals for the germinal center pathway of B cell development, EMBO J., 17, 5066, 10.1093/emboj/17.17.5066 · DOI
  59. Rankin, 2011, IL-21 receptor is critical for the development of memory B cell responses, J. Immunol., 186, 667, 10.4049/jimmunol.0903207 · DOI
  60. Reinhardt, 2009, Cytokine-secreting follicular T cells shape the antibody repertoire, Nat. Immunol., 10, 385, 10.1038/ni.1715 · DOI
  61. Samardzic, 2002, CD22 regulates early B cell development in BOB.1/OBF.1-deficient mice, Eur. J. Immunol., 32, 2481, 10.1002/1521-4141(200209)32:9<2481::AID-IMMU2481>3.0.CO;2-C · DOI
  62. Sangster, 2000, Analysis of the virus-specific and nonspecific B cell response to a persistent B-lymphotropic gammaherpesvirus, J. Immunol., 164, 1820, 10.4049/jimmunol.164.4.1820 · DOI
  63. Sauter, 1997, The B cell-specific coactivator OBF-1 (OCA-B, Bob-1) is inducible in T cells and its expression is dispensable for IL-2 gene induction, Immunobiology., 198, 207, 10.1016/S0171-2985(97)80041-1 · DOI
  64. Schreiber, 1989, Rapid detection of octamer binding proteins with ‘mini-extracts’, prepared from a small number of cells, Nucleic Acids Res., 17, 6419, 10.1093/nar/17.15.6419 · DOI
  65. Schubart, 1996, B-cell-specific coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation, Nature., 383, 538, 10.1038/383538a0 · DOI
  66. Schubart, 2001, B cell development and immunoglobulin gene transcription in the absence of Oct-2 and OBF-1, Nat. Immunol., 2, 69, 10.1038/83190 · DOI
  67. Shore, 2002, Oct-2 regulates CD36 gene expression via a consensus octamer, which excludes the co-activator OBF-1, Nucleic Acids Res., 30, 1767, 10.1093/nar/30.8.1767 · DOI
  68. Simon, 2003, Q-Gene: processing quantitative real-time RT-PCR data, Bioinformatics., 19, 1439, 10.1093/bioinformatics/btg157 · DOI
  69. Smith, 2008, Association of serum interleukin-6 concentration with a functional IL6 -6331T>C polymorphism, Clin. Chem., 54, 841, 10.1373/clinchem.2007.098608 · DOI
  70. Spanopoulou, 1994, Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice, Genes Dev., 8, 1030, 10.1101/gad.8.9.1030 · DOI
  71. Strubin, 1995, OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins, Cell., 80, 497, 10.1016/0092-8674(95)90500-6 · DOI
  72. Suto, 2008, Development and characterization of IL-21–producing CD4+ T cells, J. Exp. Med., 205, 1369, 10.1084/jem.20072057 · DOI
  73. Vijayanand, 2012, Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V, Immunity., 36, 175, 10.1016/j.immuni.2011.12.014 · DOI
  74. Vinuesa, 2011, How T cells earn the follicular rite of passage, Immunity., 35, 671, 10.1016/j.immuni.2011.11.001 · DOI
  75. Vogelzang, 2008, A fundamental role for interleukin-21 in the generation of T follicular helper cells, Immunity., 29, 127, 10.1016/j.immuni.2008.06.001 · DOI
  76. Wu, 2009, IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation, Int. Immunol., 21, 745, 10.1093/intimm/dxp041 · DOI
  77. Yi, 1996, IFN-gamma promotes IL-6 and IgM secretion in response to CpG motifs in bacterial DNA and oligodeoxynucleotides, J. Immunol., 156, 558, 10.4049/jimmunol.156.2.558 · DOI
  78. Yu, 2010, The elusive identity of T follicular helper cells, Trends Immunol., 31, 377, 10.1016/j.it.2010.07.001 · DOI
  79. Yu, 2009, The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment, Immunity., 31, 457, 10.1016/j.immuni.2009.07.002 · DOI
  80. Yusuf, 2010, Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150), J. Immunol., 185, 190, 10.4049/jimmunol.0903505 · DOI
  81. Zaretsky, 2009, T follicular helper cells differentiate from Th2 cells in response to helminth antigens, J. Exp. Med., 206, 991, 10.1084/jem.20090303 · DOI
  82. Zeng, 2007, The molecular basis of IL-21-mediated proliferation, Blood., 109, 4135, 10.1182/blood-2006-10-054973 · DOI
  83. Zotos, 2010, IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism, J. Exp. Med., 207, 365, 10.1084/jem.20091777 · DOI
  84. Zwilling, 1997, Inducible expression and phosphorylation of coactivator BOB.1/OBF.1 in T cells, Science., 277, 221, 10.1126/science.277.5323.221 · DOI

Cited by

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Metadata

Authors
Karnowski, A., Chevrier, S., Belz, G. T., Mount, A., Emslie, D., D’Costa, K., Tarlinton, D. M., Kallies, A., & Corcoran, L. M.
Affiliations
Molecular Immunology Division 1 and 2
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2012-10-08
Volume
209
Issue
11
Pages
2049-2064
ISSN
  • 1540-9538
  • 0022-1007
DOI
10.1084/jem.20111504
PMC
PMC3478936
Cited by
206
References
5
Language
en

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CoChat. (2026). Citation check: B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. https://app.cochat.ai/papers/10.1084/jem.20111504
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Karnowski, A., Chevrier, S., Belz, G. T., Mount, A., Emslie, D., D’Costa, K., Tarlinton, D. M., Kallies, A., & Corcoran, L. M. (2012). B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20111504