Our objective is to define the mechanisms that control lymphocyte trafficking in the GI tract, focusing on the colon vs. small intestines (SI), and to characterize their roles in targeting effector and memory cells to mucosal immunogens. Our underlying hypothesis is that specialized mechanisms differentiate lymphocyte trafficking along the digestive tract, and allow regional segregation and specialization of gastrointestinal immune responses.
Aim 1 : To identify colon-homing T cells, and determine whether colonic immunization imprints selective colon homing properties on responding T cells: The homing of T cells to the colon is poorly understood. Short-term homing assays will be used to identify T cell subsets that home optimally to the colon;to seek subsets that can home selectively to the colon vs. the small intestines;and to test the hypothesis that colonic immunization imprints specialized colon-selective trafficking programs on antigen-reactive T cells.
Aim 2 : To identify known and candidate novel trafficking receptors expressed by colon- and SI-homing T cell populations. Immunofluorescence and gene microarray studies will be used.
Aim 3 : To define the molecular mechanisms of T cell recruitment to the colon vs. small intestines, and the role(s) of colon- and small intestine- selective T cell chemoattractant and orphan G protein linked receptors (GPCRs): Short term homing studies using blocking monoclonal antibodies and gene-targeted lymphocytes will be used to test the hypothesized role of expressed trafficking receptors, including novel candidate colon- and SI-specific GPCRs, in T cell homing to normal or inflamed colon or SI. Mixed bone marrow chimeras will be generated to test the effects of genetic deletion of candidate GPCR SI and colon trafficking receptors on T cell repopulation and microenvironmental positioning within the GI tract. Understanding lymphocyte recruitment to normal and inflamed intestines may lead to novel therapeutic approaches in inflammatory bowel diseases, as well as providing insights that can improve methods of vaccination and monitoring of mucosal immunity to intestinal pathogens, and to HIV. 69
Immune cells need to gain access to the gut wall to provide protection against pathogenic organisms, but they can also cause pathologic inflammation for example in inflammatory bowel diseases (IBD). We propose to define the molecules that control lymphocyte trafficking from the blood circulation into the intestines, particularly those that mediate immune cell recruitment into the colon and small intestines. Understanding lymphocyte recruitment to normal and inflamed intestines may lead to novel therapeutic approaches in IBD, as well as providing insights that can improve methods of vaccination and monitoring of mucosal immunity to HIV, SARS, rotavirus and other infectious agents.
|Watchmaker, Payal B; Lahl, Katharina; Lee, Mike et al. (2014) Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat Immunol 15:98-108|
|Parra, Miguel; Herrera, Daniel; Calvo-Calle, J Mauricio et al. (2014) Circulating human rotavirus specific CD4 T cells identified with a class II tetramer express the intestinal homing receptors ?4?7 and CCR9. Virology 452-453:191-201|
|Lahl, Katharina; Sweere, Johanna; Pan, Junliang et al. (2014) Orphan chemoattractant receptor GPR15 mediates dendritic epidermal T-cell recruitment to the skin. Eur J Immunol 44:2577-81|
|Lee, Mike; Kiefel, Helena; LaJevic, Melissa D et al. (2014) Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing. Nat Immunol 15:982-95|
|Kellermayer, Zoltán; Mihalj, Martina; Lábadi, Árpád et al. (2014) Absence of Nkx2-3 homeodomain transcription factor reprograms the endothelial addressin preference for lymphocyte homing in Peyer's patches. J Immunol 193:5284-93|
|Oderup, Cecilia; LaJevic, Melissa; Butcher, Eugene C (2013) Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. J Immunol 190:6126-34|
|Deal, Emily M; Lahl, Katharina; Narvaez, Carlos F et al. (2013) Plasmacytoid dendritic cells promote rotavirus-induced human and murine B cell responses. J Clin Invest 123:2464-74|