The complementation of lymphotoxin deficiency with LIGHT, a newly discovered TNF family member, for the restoration of secondary lymphoid structure and function.
Highly organized lymphoid structures provide the intricate microenvironment essential for the mediation of the effective immune responses. Compared with lymphotoxin beta knockout mice (LTbeta-/-), LTbeta receptor knockout (LTbetaR-/-) mice present with more severely disorganized splenic structures, suggesting the potential involvement of another ligand. LIGHT, a newly identified TNF family member, is a costimulatory molecule for T cells and binds to LTbetaR and herpes virus entry mediator (HVEM) in vitro. Here, we show that the complementation of LTalpha-/- mice with a LIGHT transgene (LIGHT Tg/LTalpha-/-) leads to the restoration of secondary lymphoid tissue chemokine and T/B cell zone segregation. LIGHT Tg/LTalpha-/- mice also preserve dendritic cells, follicular dendritic cell networks, and germinal centers, though not the marginal zone. Consequently, IgG responses to soluble, but not particulate, antigens are restored, confirming the role of primary follicle and marginal zone in the responses to soluble and particulate antigens. The failure of the LIGHT transgene to rescue the defective splenic structures in LTbetaR-/- mice demonstrates that LIGHT can interact with LTbetaR in vivo. More severely disorganized splenic structures developed after blockade of endogenous LIGHT in LTbeta-/- mice. These findings uncover the potential interaction between LIGHT and one of its receptors, LTbetaR, in supporting even in the absence of LT the development and maintenance of lymphoid microenvironment.
Wang
Jing
J
Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
Foster
Amy
A
Chin
Robert
R
Yu
Ping
P
Sun
Yonglian
Y
Wang
Yang
Y
Pfeffer
Klaus
K
Fu
Yang-Xin
YX
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000096:biosynthesis; D020566:Dendritic Cells, Follicular / Q000166:cytology; D005816:Genetic Complementation Test; D018858:Germinal Center / Q000166:cytology; D008198:Lymph Nodes / Q000473:pathology*; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology; D019076:Transgenes; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha