Effects of lymphotoxin β receptor blockade on intestinal mucosal immunity

Background: Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) directs lymphocyte migration into gut-associated lymphoid tissue (GALT) through Peyer's patches (PPs). Parenteral nutrition (PN) impairs mucosal immunity by reducing PPs MAdCAM-1 expression, T and B cells in GALT, and intestinal and respiratory immunoglobulin (Ig) A levels. We previously showed that PN reduces lymphotoxin β receptor blockade (LTβR) in PPs and intestine, and that stimulation with LTβR agonist antibodies reverses these defects. To confirm that LTβR regulates transcription of MAdCAM-1 message and more fully understand the effects of LTβR on MAdCAM-1 function within the mucosal immune system, we studied the effect of LTβR blockade with a chimeric LTβR Ig-fusion protein on MAdCAM-1 mRNA levels, PP lymphocyte mass and IgA levels in the intestinal and respiratory tracts. Methods: Mice were cannulated and killed 3 days after receiving chow + control Ig, chow + LTβR-Ig fusion protein (100 μg IV), or PN + control Ig. The PPs of half of the animals were processed for lymphocyte count, and the other half were processed for complementary DNA and subsequent polymerase chain reaction (PCR). mRNA levels of MAdCAM-1 were determined by real-time PCR; intestinal and respiratory IgA levels were measured by ELISA. Results: PN significantly reduced PP lymphocyte mass, MAdCAM-1 mRNA, and intestinal IgA. As anticipated, LTβR blockade significantly decreased PP cells and MAdCAM-1 mRNA, but not intestinal IgA because chow feeding was maintained. Both LTβR blockade and PN decreased nasal IgA, but not significantly. Conclusions: LTβR blockade in chow animals significantly reduces transcription of MAdCAM-1 gene and PPs lymphocyte mass. These data implicate inadequate LTβR signaling as a major mechanism for decreased GALT cells with lack of enteral stimulation, and further establish the role of LTβR in the mucosal immune system.