The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/1/403/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 2, January 18, 1999 403-412

Articles

Lymphotoxin {alpha}/β and Tumor Necrosis Factor Are Required for Stromal Cell Expression of Homing Chemokines in B and T Cell Areas of the Spleen

Vu N. Ngo*, Heinrich Korner§, Michael D. Gunn{ddagger}, Kerstin N. Schmidt*, D. Sean Riminton§, Max D. Cooper||, Jeffrey L. Browning, Jonathon D. Sedgwick{ddagger},§, and Jason G. Cyster*

From the * Department of Microbiology and Immunology, and {ddagger} Cardiovascular Research Institute, University of California San Francisco, San Francisco, California 94143; § Centenary Institute of Cancer Medicine and Cell Biology, Sydney, 2050 New South Wales, Australia; || Howard Hughes Medical Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294; and Biogen Inc., Cambridge, Massachusetts 02142

Mice deficient in the cytokines tumor necrosis factor (TNF) or lymphotoxin (LT) {alpha}/β 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)-, LT{alpha}- and LTβ-deficient mice. Treatment of adult mice with antagonists of LT{alpha}1β2 also leads to decreased BLC expression. These findings indicate that LT{alpha}1β2 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 LT{alpha}-, and LTβ-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 LT{alpha}1β2 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.

Key Words: lymphoid tissue • follicle • lymphocyte • follicular dendritic cell • dendritic cell

Address correspondence to Jason G. Cyster, Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus St., San Francisco, CA 94143-0414. Phone: 415-502-6427; Fax: 415-502-8424; E-mail: cyster{at}itsa.ucsf.edu

J.D. Sedgwick, H. Korner, and D.S. Riminton were supported by grants from the National Health and Medical Research Council of Australia and the National Multiple Sclerosis Society of Australia. J.G. Cyster is a Pew Scholar in the biomedical sciences. This work was supported in part by National Institutes of Health grant AI40098 to J.G. Cyster and by Howard Hughes Medical Institute grant 76296-549901 to the University of California San Francisco School of Medicine.

J.D. Sedgwick's present address is DNAX Research Institute, 901 California Ave., Palo Alto, CA 94304-1104.

Abbreviations used: BCR, B cell receptor; BLC, B lymphocyte chemoattractant; DC, dendritic cell; EBI-1, Epstein Barr virus–induced molecule 1; ELC, EBI-1 ligand chemokine; EF, elongation factor; ES, embryonic stem; FDC, follicular DC; LT, lymphotoxin; MAdCAM, mucosal addressin cell adhesion molecule; MMM, marginal metallophilic macrophage; MZM, marginal zone macrophage; RAG, recombination activating gene; SDF, stromal cell–derived factor; SLC, secondary lymphoid tissue chemokine.


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