Toll-like receptor 9, transmembrane activator and calcium-modulating cyclophilin ligand interactor, and CD40 synergize in causing B-cell activation

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• 作者：Esra  ; Ozcan MD^a ; Ingrid  ; Rauter PhD^a ; Lilit  ; Garibyan MD ; PhD^a ; Stacey R.  ; Dillon PhD^b ; Raif S.  ; Geha MD^a ;   ; ^{raif.geha@childrens.harvard.edu}
• 关键词：Toll-like receptor 9 ; CD40 ; transmembrane activator and calcium-modulating cyclophilin ligand interactor ; class-switch recombination ; plasma cell ; immunoglobulin ; B cells
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2011
• 出版时间：September 2011
• 年：2011
• 卷：128
• 期：3
• 页码：601-609.e4
• 全文大小：1501 K
• ISSN：S0091674911007597

文摘

Background

B cells receive activating signals from T cells through CD40, from microbial DNA through Toll-like receptor (TLR) 9, and from dendritic cells through transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI). TLR9 and CD40 ligation augment TACI-driven B-cell activation, but only the mechanism of synergy between CD40 and TACI has been explored. Synergy between CD40 and TLR9 in B-cell activation is controversial.

Objective

We sought to examine the mechanisms by which TLR9 modulates CD40- and TACI-mediated activation of B cells and to determine whether all 3 receptors synergize to activate B cells.

Methods

Naive murine B cells and human PBMCs were stimulated with combinations of anti-CD40, CpG, and a proliferation inducing ligand in the presence of IL-4. Proliferation was measured by means of tritiated thymidine incorporation. Immunoglobulin production was measured by means of ELISA. Class-switch recombination (CSR) was examined by measuring mRNA for germline transcripts, activation-induced cytidine deaminase (AICDA), and mature immunoglobulin transcripts. Plasma cell differentiation was examined by using syndecan-1/CD138 staining and mRNA expression of B lymphocyte–induced maturation protein 1 (Blimp-1).

Results

TLR9 synergized with CD40 and TACI in driving CSR and inducing IgG₁ and IgE secretion by naive murine B cells and synergized with TACI in driving B-cell proliferation and plasma cell differentiation. All 3 receptors synergized together in driving murine B-cell proliferation, CSR, plasma cell differentiation, and IgG₁ and IgE secretion. TLR9 synergized with CD40 and TACI in driving IgG secretion in IL-4–stimulated human B cells.

Conclusion

Signals from TLR9, TACI, and CD40 are integrated to promote B-cell activation and differentiation.