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IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses.

Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, Verma NK, Smyth MJ, Rigby RJ, Vinuesa CG - J. Exp. Med. (2010)

Bottom Line: To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells.IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1(+) GC B cells but did not affect formation of early memory B cells.In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.

View Article: PubMed Central - HTML - PubMed

Affiliation: John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.

ABSTRACT
During T cell-dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell-intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell-autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1(+) GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.

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Lack of IL-21 does not alter Salmonella pathogen clearance or production of anti-Salmonella humoral immunity. (A) ELISA analysis of the titers of Salmonella-specific IgM, IgG1, IgG2ab, IgG2b, and IgG3 in sera from Il21+/+(white bars) and Il21−/− (black bars) mice 12 d after Salmonella infection. (B and C) Dot plots of spleen weights (B) and the number of bacteria per liver (C) in Il21+/+ and Il21−/− mice 12 d after infection with Salmonella. Data are representative of two independent experiments. Each symbol represents one mouse and tops of bars are drawn through the median values. nd, not detected.
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fig6: Lack of IL-21 does not alter Salmonella pathogen clearance or production of anti-Salmonella humoral immunity. (A) ELISA analysis of the titers of Salmonella-specific IgM, IgG1, IgG2ab, IgG2b, and IgG3 in sera from Il21+/+(white bars) and Il21−/− (black bars) mice 12 d after Salmonella infection. (B and C) Dot plots of spleen weights (B) and the number of bacteria per liver (C) in Il21+/+ and Il21−/− mice 12 d after infection with Salmonella. Data are representative of two independent experiments. Each symbol represents one mouse and tops of bars are drawn through the median values. nd, not detected.

Mentions: Previous reports have revealed that IL-21 can support plasma cell differentiation from naive B cells in vitro (Ettinger et al., 2007). In vivo, large numbers of BLIMP-1+ plasma cells are found in IL-21 transgenic mice (Ozaki et al., 2004), but this study could not differentiate whether the plasma cells were of follicular (GC) or extrafollicular origin. IL-21–producing T cells have been reported to colocalize with extrafollicular plasma cell foci in the autoimmune lpr mouse strain (Odegard et al., 2008). To investigate whether IL-21 is required for an extrafollicular response against an infectious pathogen, we chose Salmonella infection as a model. The initial humoral response to Salmonella species infection requires CD4+ T cell help, and the early phase of the antibody response is derived purely from extrafollicular plasma cells; GCs do not form until at least 5 wk after infection (Hess et al., 1996; Yrlid and Wick, 2000; Cunningham et al., 2007). Il21+/+ and Il21−/− mice were infected with live attenuated Salmonella enterica serovar Dublin strain SL5631, which also elicits a CD28-dependent antibody response derived exclusively from extrafollicular foci and dominated by IgG2ab production (Linterman et al., 2009a). Consistent with previous reports, GC responses were absent 12 d after Salmonella infection (Fig. S4). There was no difference in the amount of Salmonella-specific IgM, IgG2ab, IgG2b, or IgG3 between Il21+/+ and Il21−/− mice (Fig. 6 A). Bacterial clearance was also intact in the absence of IL-21 (Fig. 6, B and C). These data demonstrate that normal extrafollicular antibody responses can be achieved in the absence of IL-21.


IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses.

Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, Verma NK, Smyth MJ, Rigby RJ, Vinuesa CG - J. Exp. Med. (2010)

Lack of IL-21 does not alter Salmonella pathogen clearance or production of anti-Salmonella humoral immunity. (A) ELISA analysis of the titers of Salmonella-specific IgM, IgG1, IgG2ab, IgG2b, and IgG3 in sera from Il21+/+(white bars) and Il21−/− (black bars) mice 12 d after Salmonella infection. (B and C) Dot plots of spleen weights (B) and the number of bacteria per liver (C) in Il21+/+ and Il21−/− mice 12 d after infection with Salmonella. Data are representative of two independent experiments. Each symbol represents one mouse and tops of bars are drawn through the median values. nd, not detected.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2822609&req=5

fig6: Lack of IL-21 does not alter Salmonella pathogen clearance or production of anti-Salmonella humoral immunity. (A) ELISA analysis of the titers of Salmonella-specific IgM, IgG1, IgG2ab, IgG2b, and IgG3 in sera from Il21+/+(white bars) and Il21−/− (black bars) mice 12 d after Salmonella infection. (B and C) Dot plots of spleen weights (B) and the number of bacteria per liver (C) in Il21+/+ and Il21−/− mice 12 d after infection with Salmonella. Data are representative of two independent experiments. Each symbol represents one mouse and tops of bars are drawn through the median values. nd, not detected.
Mentions: Previous reports have revealed that IL-21 can support plasma cell differentiation from naive B cells in vitro (Ettinger et al., 2007). In vivo, large numbers of BLIMP-1+ plasma cells are found in IL-21 transgenic mice (Ozaki et al., 2004), but this study could not differentiate whether the plasma cells were of follicular (GC) or extrafollicular origin. IL-21–producing T cells have been reported to colocalize with extrafollicular plasma cell foci in the autoimmune lpr mouse strain (Odegard et al., 2008). To investigate whether IL-21 is required for an extrafollicular response against an infectious pathogen, we chose Salmonella infection as a model. The initial humoral response to Salmonella species infection requires CD4+ T cell help, and the early phase of the antibody response is derived purely from extrafollicular plasma cells; GCs do not form until at least 5 wk after infection (Hess et al., 1996; Yrlid and Wick, 2000; Cunningham et al., 2007). Il21+/+ and Il21−/− mice were infected with live attenuated Salmonella enterica serovar Dublin strain SL5631, which also elicits a CD28-dependent antibody response derived exclusively from extrafollicular foci and dominated by IgG2ab production (Linterman et al., 2009a). Consistent with previous reports, GC responses were absent 12 d after Salmonella infection (Fig. S4). There was no difference in the amount of Salmonella-specific IgM, IgG2ab, IgG2b, or IgG3 between Il21+/+ and Il21−/− mice (Fig. 6 A). Bacterial clearance was also intact in the absence of IL-21 (Fig. 6, B and C). These data demonstrate that normal extrafollicular antibody responses can be achieved in the absence of IL-21.

Bottom Line: To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells.IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1(+) GC B cells but did not affect formation of early memory B cells.In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.

View Article: PubMed Central - HTML - PubMed

Affiliation: John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.

ABSTRACT
During T cell-dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell-intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell-autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1(+) GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.

Show MeSH
Related in: MedlinePlus