Expression of lymphotoxin beta governs immunity at two distinct levels

interaction of lymphotoxin alpha(1)beta(2) (LT alpha(1)beta(2)) with its receptor is key for the generation and maintenance of secondary lymphoid organ microstructure. We used mice, conditionally deficient for LT beta on different lymphocyte subsets to determine how the LT beta-dependent lymphoid structure influences immune reactivity. All conditionally LT beta-deficient mice mounted normal immune responses against vesicular stomatitis virus (VSV), and were protected against lymphocytic choriomeningitis virus (LCMV). In contrast, they exhibited reduced immune responses against non-replicating antigens. Completely LT beta-deficient mice failed to retain VSV in the marginal zone and died from VSV infections, and they became virus carriers following infection with the non-cytopathic LCMV, which was correlated with defective virus replication in dendritic cells. It was ruled out that LT beta expression on lymphocytes influenced their activation, homing capacity, or maturation. We therefore conclude that LT beta expression influences immune reactivity at two distinct levels: (i) Expression of LT beta on lymphocytes enhances the induction of immune responses against limiting amounts of antigen. (ii) Expression of LT beta on non-lymphocytes governs antiviral immunity by enhancing antigen presentation on antigen-presenting cells. This prevents cytotoxic T lymphocytes exhaustion or death of the host by uncontrolled virus spread.