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 i n CXC chemokine receptor 5 (CXCR5), a receptor for B lymphocyte chemoattrac tant (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 LT beta-deficient mice. Treatment of adult mice w ith antagonists of LT alpha 1 beta 2 also leads to decreased BLC expression . These findings indicate that LT alpha 1 beta 2 and TNF have a role upstre am of BLC/CXCR5 in the process of follicle formation. In addition to disrup ted follicles, LT-deficient animals have disorganized T zones. Expression o f the T cell attractant, secondary lymphoid tissue chemokine (SLC), by T zo ne stromal cells is found to be markedly depressed in LT alpha-, and LT bet a-deficient mice. Expression of the SLC-related chemokine, Epstein Barr vir us-induced molecule 1 Ligand chemokine (ELC), is also reduced. Exploring th e basis for the reduced SLC expression led to identification of further dis ruptions in T zone stromal cells. Together these findings indicate that LT alpha 1 beta 2 and TNF are required for the development and function of B a nd T zone stromal cells that make chemokines necessary for lymphocyte compa rtmentalization in the spleen.