Chronic CD70-driven costimulation impairs IgG responses by instructing T cells to inhibit germinal center B cell formation through FasL-Fas interactions.
CD70 provides costimulation that enhances effector T cell differentiation upon binding of its receptor, CD27. During chronic immune activation, CD70 is constitutively expressed on activated immune cells, and this induces T cell-driven disruption of neutralizing Ab responses via an unknown mechanism. We used CD70-transgenic mice to investigate the effect of constitutive expression of CD70 on T cell-dependent B cell responses. CD70 induced up-regulation of the B cell follicle homing chemokine receptor CXCR5 on T cells, enabling not only CD4 but also CD8 T cells to infiltrate the B cell follicles. CD70-transgenic mice failed to develop productive germinal center formation and displayed impaired IgG Ab responses. Defective germinal center B cell differentiation was critically dependent on CD70-mediated CD27 signaling in T cells, and involved Fas-dependent impairment of germinal center B cell differentiation. Thus, CD70-driven costimulation enables T cells to terminate B cell responses, thereby compromising durable Ab production. Our findings imply that the CD70- and CD27-driven costimulatory axis may be involved in shutdown of B cell responses before clearance of Ag. Because CD70 is expressed constitutively in chronic viral infections such as HIV-1 infection, this mechanism may also contribute to defects in humoral immunity associated with this disease.
Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
Cathrien R L
CR
Beishuizen
Natasja A M
NA
Kragten
Louis
L
Boon
Martijn A
MA
Nolte
Rene A W
RA
van Lier
Klaas P J M
KP
van Gisbergen
D019264:Adoptive Transfer; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D053282:CD27 Ligand / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology*; D006241:Haptens; D006433:Hemocyanins / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D054380:Receptors, CXCR5 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D000914:Antibodies, Viral; D053282:CD27 Ligand; C513179:CXCR5 protein, mouse; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D006241:Haptens; D007074:Immunoglobulin G; D054380:Receptors, CXCR5; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019014:fas Receptor; C054401:trinitrophenyl keyhole limpet hemocyanin; D006433:Hemocyanins