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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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IL-21–deficient mice form Tfh cells after immunization, but their maintenance is impaired. (A) Flow cytometric contour plots and graphical analysis of CXCR5+PD-1+ Tfh cells gated on CD4+ B220− live lymphocytes from Il21+/+ and Il21−/− mice at the indicated time points after SRBC immunization (percentages are shown). (B) Photomicrographs of spleen sections taken from Il21+/+ (top) and Il21−/− (bottom) mice 8 d after immunization with SRBCs. In all panels, IgD is stained in brown; blue color stains indicate PNA binding (left), CD3 (middle), and PD-1 (right). Bars, 200 µm. Statistically significant differences are indicated (*, P ≤ 0.05). Data are representative of two independent experiments, each symbol represents one mouse, and tops of bars are drawn through the median values. ns, not significant.
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fig2: IL-21–deficient mice form Tfh cells after immunization, but their maintenance is impaired. (A) Flow cytometric contour plots and graphical analysis of CXCR5+PD-1+ Tfh cells gated on CD4+ B220− live lymphocytes from Il21+/+ and Il21−/− mice at the indicated time points after SRBC immunization (percentages are shown). (B) Photomicrographs of spleen sections taken from Il21+/+ (top) and Il21−/− (bottom) mice 8 d after immunization with SRBCs. In all panels, IgD is stained in brown; blue color stains indicate PNA binding (left), CD3 (middle), and PD-1 (right). Bars, 200 µm. Statistically significant differences are indicated (*, P ≤ 0.05). Data are representative of two independent experiments, each symbol represents one mouse, and tops of bars are drawn through the median values. ns, not significant.

Mentions: We investigated the kinetics of Tfh cell formation after SRBC immunization in IL-21–deficient mice by enumerating CXCR5highPD-1high CD4+ Tfh cells by flow cytometry on days 0, 6, 8, and 14 after SRBC immunization. In the absence of immunization, there were fewer background Tfh cells in Il21−/− compared with Il21+/+ mice (Fig. 2 A). We observed normal generation of Tfh cells in Il21−/− mice, with equivalent proportions on day 6 after immunization compared with Il21+/+ mice (Fig. 2 A). Although formation was normal, there was a more rapid decline in Tfh cell numbers in Il21−/− mice (Fig. 2 A). There was a slight decrease in the total number of CD4+ cells in the absence of IL-21 (Fig. S1 C), although this was not statistically significant.


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)

IL-21–deficient mice form Tfh cells after immunization, but their maintenance is impaired. (A) Flow cytometric contour plots and graphical analysis of CXCR5+PD-1+ Tfh cells gated on CD4+ B220− live lymphocytes from Il21+/+ and Il21−/− mice at the indicated time points after SRBC immunization (percentages are shown). (B) Photomicrographs of spleen sections taken from Il21+/+ (top) and Il21−/− (bottom) mice 8 d after immunization with SRBCs. In all panels, IgD is stained in brown; blue color stains indicate PNA binding (left), CD3 (middle), and PD-1 (right). Bars, 200 µm. Statistically significant differences are indicated (*, P ≤ 0.05). Data are representative of two independent experiments, each symbol represents one mouse, and tops of bars are drawn through the median values. ns, not significant.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig2: IL-21–deficient mice form Tfh cells after immunization, but their maintenance is impaired. (A) Flow cytometric contour plots and graphical analysis of CXCR5+PD-1+ Tfh cells gated on CD4+ B220− live lymphocytes from Il21+/+ and Il21−/− mice at the indicated time points after SRBC immunization (percentages are shown). (B) Photomicrographs of spleen sections taken from Il21+/+ (top) and Il21−/− (bottom) mice 8 d after immunization with SRBCs. In all panels, IgD is stained in brown; blue color stains indicate PNA binding (left), CD3 (middle), and PD-1 (right). Bars, 200 µm. Statistically significant differences are indicated (*, P ≤ 0.05). Data are representative of two independent experiments, each symbol represents one mouse, and tops of bars are drawn through the median values. ns, not significant.
Mentions: We investigated the kinetics of Tfh cell formation after SRBC immunization in IL-21–deficient mice by enumerating CXCR5highPD-1high CD4+ Tfh cells by flow cytometry on days 0, 6, 8, and 14 after SRBC immunization. In the absence of immunization, there were fewer background Tfh cells in Il21−/− compared with Il21+/+ mice (Fig. 2 A). We observed normal generation of Tfh cells in Il21−/− mice, with equivalent proportions on day 6 after immunization compared with Il21+/+ mice (Fig. 2 A). Although formation was normal, there was a more rapid decline in Tfh cell numbers in Il21−/− mice (Fig. 2 A). There was a slight decrease in the total number of CD4+ cells in the absence of IL-21 (Fig. S1 C), although this was not statistically significant.

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