Limits...
IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism.

Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, Kallies A, Corcoran LM, Godfrey DI, Toellner KM, Smyth MJ, Nutt SL, Tarlinton DM - J. Exp. Med. (2010)

Bottom Line: Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen.The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype.IL-21 thus controls fate choices of GC B cells directly.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.

ABSTRACT
Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.

Show MeSH

Related in: MedlinePlus

IL-21 is not essential for Tfh cell development. (A) Representative flow cytometry gating for identifying Tfh cells among splenocytes. CD4+TCR-β+ cells were assessed for expression of PD1 and CXCR5 to resolve Tfh cells in C57BL/6 and IL-21−/− mice. Percentages are of the CD4+TCR-β+ population. (B) Frequency of Tfh cells (CD4+TCR-β+PD1+CXCR5+) in C57BL/6, IL-21−/−, and IL-21R−/− mice at times indicated after immunization. Values are mean frequency of two to six mice per time point from at least two experiments and error bars are ± SD. (C) Immunohistochemical staining of CD3+ cells (blue) in the GCs of the spleens from day 14 immunized C57BL/6 and IL-21R−/− mice. The example shown is representative of at least four mice from two experiments for each genotype. B cell follicles were revealed with IgD (brown). Bars, 100 µm.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC2822601&req=5

fig4: IL-21 is not essential for Tfh cell development. (A) Representative flow cytometry gating for identifying Tfh cells among splenocytes. CD4+TCR-β+ cells were assessed for expression of PD1 and CXCR5 to resolve Tfh cells in C57BL/6 and IL-21−/− mice. Percentages are of the CD4+TCR-β+ population. (B) Frequency of Tfh cells (CD4+TCR-β+PD1+CXCR5+) in C57BL/6, IL-21−/−, and IL-21R−/− mice at times indicated after immunization. Values are mean frequency of two to six mice per time point from at least two experiments and error bars are ± SD. (C) Immunohistochemical staining of CD3+ cells (blue) in the GCs of the spleens from day 14 immunized C57BL/6 and IL-21R−/− mice. The example shown is representative of at least four mice from two experiments for each genotype. B cell follicles were revealed with IgD (brown). Bars, 100 µm.

Mentions: The abnormal development of ASC and GC in IL-21−/− and IL-21R−/− mice raised the question of the nature of the T cell help in these mice (Nurieva et al., 2008; Vogelzang et al., 2008). We examined spleens of immunized control, IL-21−/−, and IL-21R−/− mice for CD4+ T cells coexpressing CXCR5 and PD1, a combination of markers which is widely used in identifying Tfh cells (Vinuesa et al., 2005), and found such cells in all groups, albeit at somewhat variable frequency at the time points assessed (Fig. 4, A and B). Interpreting the frequency of Tfh in IL-21 knockout mice, however, is complicated by the GC B cell phenotype in these mice and the possibility that Tfh development, persistence, or localization is influenced by the presence of GC B cells. We therefore used histology to determine if CD3+ cells were in fact located within the GC of IL-21–deficient mice at day 14. Such cells were clearly visible and appeared to be distributed equivalently with those in controls (Fig. 4 C). These results suggest that although IL-21 may have a role in Tfh expansion or persistence, it is not required for their appearance, localization, or ability to support GC formation.


IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism.

Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, Kallies A, Corcoran LM, Godfrey DI, Toellner KM, Smyth MJ, Nutt SL, Tarlinton DM - J. Exp. Med. (2010)

IL-21 is not essential for Tfh cell development. (A) Representative flow cytometry gating for identifying Tfh cells among splenocytes. CD4+TCR-β+ cells were assessed for expression of PD1 and CXCR5 to resolve Tfh cells in C57BL/6 and IL-21−/− mice. Percentages are of the CD4+TCR-β+ population. (B) Frequency of Tfh cells (CD4+TCR-β+PD1+CXCR5+) in C57BL/6, IL-21−/−, and IL-21R−/− mice at times indicated after immunization. Values are mean frequency of two to six mice per time point from at least two experiments and error bars are ± SD. (C) Immunohistochemical staining of CD3+ cells (blue) in the GCs of the spleens from day 14 immunized C57BL/6 and IL-21R−/− mice. The example shown is representative of at least four mice from two experiments for each genotype. B cell follicles were revealed with IgD (brown). Bars, 100 µm.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2822601&req=5

fig4: IL-21 is not essential for Tfh cell development. (A) Representative flow cytometry gating for identifying Tfh cells among splenocytes. CD4+TCR-β+ cells were assessed for expression of PD1 and CXCR5 to resolve Tfh cells in C57BL/6 and IL-21−/− mice. Percentages are of the CD4+TCR-β+ population. (B) Frequency of Tfh cells (CD4+TCR-β+PD1+CXCR5+) in C57BL/6, IL-21−/−, and IL-21R−/− mice at times indicated after immunization. Values are mean frequency of two to six mice per time point from at least two experiments and error bars are ± SD. (C) Immunohistochemical staining of CD3+ cells (blue) in the GCs of the spleens from day 14 immunized C57BL/6 and IL-21R−/− mice. The example shown is representative of at least four mice from two experiments for each genotype. B cell follicles were revealed with IgD (brown). Bars, 100 µm.
Mentions: The abnormal development of ASC and GC in IL-21−/− and IL-21R−/− mice raised the question of the nature of the T cell help in these mice (Nurieva et al., 2008; Vogelzang et al., 2008). We examined spleens of immunized control, IL-21−/−, and IL-21R−/− mice for CD4+ T cells coexpressing CXCR5 and PD1, a combination of markers which is widely used in identifying Tfh cells (Vinuesa et al., 2005), and found such cells in all groups, albeit at somewhat variable frequency at the time points assessed (Fig. 4, A and B). Interpreting the frequency of Tfh in IL-21 knockout mice, however, is complicated by the GC B cell phenotype in these mice and the possibility that Tfh development, persistence, or localization is influenced by the presence of GC B cells. We therefore used histology to determine if CD3+ cells were in fact located within the GC of IL-21–deficient mice at day 14. Such cells were clearly visible and appeared to be distributed equivalently with those in controls (Fig. 4 C). These results suggest that although IL-21 may have a role in Tfh expansion or persistence, it is not required for their appearance, localization, or ability to support GC formation.

Bottom Line: Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen.The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype.IL-21 thus controls fate choices of GC B cells directly.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.

ABSTRACT
Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.

Show MeSH
Related in: MedlinePlus