A T cell-Dependent Mechanism for the Induction of Human Mucosal Homing Immunoglobulin A-Secreting Plasmablasts

Melissa Dullaers, Dapeng Li, Yaming Xue, Ling Ni, Ingrid Gayet, Rimpei Morita,

Hideki Ueno, Karolina Anna Palucka, Jacques Banchereau, and SangKon Oh1.

2009. Immunity. 30, 120-129

Speaker: Wen-Hsin Yao (姚文欣)                                         Time: 15:10~16:00, Jun. 3, 2009

Commentator: Dr. Chi-Chang Shieh (謝奇璋 教授)           Place: Room 601

Abstract:

Immunoglobulin A (IgA) plays a predominant defending role in mucosal surface. It can be secreted in a T cell-independent (TI) and -dependent (TD) pathway by IgA-plasma cells (IgA-PCs) ¹. TD pathway happens in germinal center (GC) and can generate high affinity IgA. Follicular helper T cells (Tfh) are central for GC formation and provide signals and cytokines, such as IL-10, TGF-β, and IL-21, for B cells differentiation². However, how these factors induce large amount of IgA-PCs and make them homing to mucosal site are not clear. To understand TD factors involved in B cells differentiation, the authors combined anti-IgM, CpG, anti-CD-40, and IL-2 to activate naïve IgD⁺CD27^-B cells, and then mimicked different steps of TD activated B cells response in vitro. The data showed that TGF-β prolonged IL-21-induced B cells proliferation, which subsequently increased the amounts of plasmablasts (PB) and memory cells. After combining TGF-β and IL-21 treatments for 6 and 12 days, these B cells expressed mainly surface and secreted IgA, respectively, rather than IgG, which was induced by IL-21 treatment alone. In addition, only combining these two cytokines strongly upregulated V_HDJ_H-C_Hα₁ and V_HDJ_H-C_Hα₁ transcripts, indicating class swiching to IgA1 and IgA2. These data suggested that TGF-β can override IL-21-induced IgG class switch and skew toward IgA switching. CCR10 is a mucosal homing receptor. The tonsil section staining showed that most IgA⁺ cells in GC expressed CCR10, and corresponding to this finding, combining TGF-β and IL-21 treatments in vitro upregulated CCR10 expression of activated B cells. Finally, the authors cocultured the activated B cells with autologous isolated CXCR5⁺ Tfh. They found that Tfhs stimulated B cells to differentiate into CCR10⁺IgA⁺PBs. In conclusion, TGF-β and IL-21 synergistically stimulate activated B cells to undergo proliferation and differentiation into IgA-PBs, and to upregulate CCR10 for PBs homing to mucosal surface.

References

1.      Cerutti A. The regulation of IgA class switching. Nat Rev Immunol. 8(6), 421-34 (2008)

2.      King C, et al. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu. Rev. Immunol. 26, 741-766 (2008)