Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen.
Mice deficient in the cytokines tumor necrosis factor (TNF) or lymphotoxin (LT) alpha/beta lack polarized B cell follicles in the spleen. Deficiency in CXC chemokine receptor 5 (CXCR5), a receptor for B lymphocyte chemoattractant (BLC), also causes loss of splenic follicles. Here we report that BLC expression by follicular stromal cells is defective in TNF-, TNF receptor 1 (TNFR1)-, LTalpha- and LTbeta-deficient mice. Treatment of adult mice with antagonists of LTalpha1beta2 also leads to decreased BLC expression. These findings indicate that LTalpha1beta2 and TNF have a role upstream of BLC/CXCR5 in the process of follicle formation. In addition to disrupted follicles, LT-deficient animals have disorganized T zones. Expression of the T cell attractant, secondary lymphoid tissue chemokine (SLC), by T zone stromal cells is found to be markedly depressed in LTalpha-, and LTbeta-deficient mice. Expression of the SLC-related chemokine, Epstein Barr virus-induced molecule 1 ligand chemokine (ELC), is also reduced. Exploring the basis for the reduced SLC expression led to identification of further disruptions in T zone stromal cells. Together these findings indicate that LTalpha1beta2 and TNF are required for the development and function of B and T zone stromal cells that make chemokines necessary for lymphocyte compartmentalization in the spleen.
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Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California 94143, USA.
Korner
H
H
Gunn
M D
MD
Schmidt
K N
KN
Riminton
D S
DS
Cooper
M D
MD
Browning
J L
JL
Sedgwick
J D
JD
Cyster
J G
JG
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D017403:In Situ Hybridization; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C513179:CXCR5 protein, mouse; D015815:Cell Adhesion Molecules; D054382:Chemokine CXCL13; D019743:Chemokines, CXC; C486386:Cxcl13 protein, mouse; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D014409:Tumor Necrosis Factor-alpha; D019204:GTP-Binding Proteins