Work from our previous studies has shown that the nasal-associated lymphoid tissue (NALT) and the various head and neck lymph nodes (LN) express unique addressin patterns. The high endothelial venules (HEV) from these lymphoid tissues do not resemble Peyer's patch (PP) HEV with the extensive presence of MAdCAM-1. Instead, the peripheral node addressin (PNAd) dominates these tissues, suggesting an alternative mode of mucosal lymphocyte homing especially in light of past studies by other investigators showing that mucosal B cell migration to small intestinal lamina propria (iLP) is dependent upon MAdCAM- 1-alpha4beta7 interactions, and to a lesser degree, upon L-selectin. In fact, effector B cell immunity segregated with the alpha4beta7/high phenotype. Herein this application, we propose that at least two other mucosal B cell subsets exist that are not alpha4beta7/high.One B cell subset is identified as L-selectin/low alpha4beta7/low, the other, alphaEbeta7+. In mice intranasally (i.n.) immunized with cholera toxin (CT), we show primarily L-selectin/low alpha4beta7/low effector B cells in the nasal passages (NP), reproductive tract (RT), and submaxillary gland (SMG). Evaluation of i.n. CT-immunized L-selectin-deficient mice show an absence of mucosal effector B ceils in the NP, but iLP responses were maintained as alphaEbeta7+, not alpha4beta7/high. Collectively, these data suggest that L-selectin is important for the migration of antigen (Ag)-specific effector B cells in nonintestinal mucosal tissues. Thus, this proposal will characterize the functional attributes of L-selectinlow alpha4beta7/low and alphaEbeta7+B cells subsequent to i.n. or oral immunization with CT. Studies in Specific Aim 1 will determine the relative importance of L-selectin and alpha4beta7 to the development of both inductive and effector B cell immunity subsequent to i.n. or oral immunization. Studies in Specific Aim 2 will determine determine if the described novel L-selectin/low alpha4beta7/low or alphaEbeta7+ B cells can home to nonintestinal as well as intestinal mucosal effector tissues. Studies in Specific Aim 3 will determine which B cell subset, L-selectin/low alpha4beta7/low or alphaEbeta7+, is protective against i.n. challenge with CT. From this work, we will learn how routes of immunizations can be used to effectively target vaccines to nonintestinal mucosal sites.
|Pascual, David W; Wang, Xinhai; Kochetkova, Irina et al. (2008) The absence of lymphoid CD8+ dendritic cell maturation in L-selectin-/- respiratory compartment attenuates antiviral immunity. J Immunol 181:1345-56|
|Pascual, D W; Riccardi, C; Csencsits-Smith, K (2008) Distal IgA immunity can be sustained by alphaEbeta7+ B cells in L-selectin-/- mice following oral immunization. Mucosal Immunol 1:68-77|
|Pascual, David W (2007) Vaccines are for dinner. Proc Natl Acad Sci U S A 104:10757-8|