IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells

被引:167
作者
Batten, Marcel [3 ,4 ]
Ramamoorthi, Nandhini [1 ]
Kljavin, Noelyn M. [1 ]
Ma, Cindy S. [3 ,4 ]
Cox, Jennifer H. [1 ]
Dengler, Hart S. [1 ]
Danilenko, Dimitry M. [2 ]
Caplazi, Patrick [2 ]
Wong, Melanie [5 ]
Fulcher, David A. [6 ]
Cook, Matthew C. [7 ,8 ,9 ]
King, Cecile [3 ]
Tangye, Stuart G. [3 ,4 ]
de Sauvage, Frederic J. [1 ]
Ghilardi, Nico [1 ]
机构
[1] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA
[2] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA
[3] Garvan Inst Med Res, Sydney, NSW 2010, Australia
[4] Univ NSW, St Vincents Clin Sch, Sydney, NSW, Australia
[5] Childrens Hosp Westmead, Dept Immunol, Sydney, NSW, Australia
[6] Westmead Hosp, Dept Immunol, Inst Clin Pathol & Med Res, Sydney, NSW, Australia
[7] Australian Natl Univ, Sch Med, Canberra, ACT 0200, Australia
[8] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 2601, Australia
[9] Canberra Hosp, Dept Immunol, Canberra, ACT 2601, Australia
基金
英国医学研究理事会;
关键词
SYSTEMIC-LUPUS-ERYTHEMATOSUS; CENTRAL-NERVOUS-SYSTEM; B-CELLS; IMMUNE-RESPONSES; GENE-EXPRESSION; LYMPHOID-TISSUE; CUTTING EDGE; RECEPTOR; MICE; DIFFERENTIATION;
D O I
10.1084/jem.20100064
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (T-FH) cells. T-FH cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of T-FH cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of T-FH cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4(+) T cells and the expression of T-FH cell phenotypic markers. In vivo, expression of the IL-27R alpha chain is required to support IL-21 production and T-FH cell survival in a T cell-intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in II27ra(-/-) mice. Together, our data show a nonredundant role for IL-27 in the development of T cell-dependent antibody responses.
引用
收藏
页码:2895 / 2906
页数:12
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