To better understand the roles of γδ T cells in mucosal infection, we utilized Salmonella enterica serovar Typhimurium (Salmonella serovar Typhimurium) infection in cattle as it closely approximates Salmonella serovar Typhimurium-induced enterocolitis in humans. Protein and gene expression in αβ and γδ T cells derived from lymphatic ducts draining the gut mucosa in Salmonella serovar Typhimurium infected calves were analyzed. In calves with enterocolitis, general gene expression trends in γδ T cells suggested subtle activation and innate response, whereas αβ T cells were relatively quiescent following Salmonella serovar Typhimurium infection. An increase in IL-2Rα expression on γδ T cells from infected calves and results from in vitro assays suggested that γδ T cells were primed by Salmonella serovar Typhimurium LPS to better respond to IL-2 and IL-15. Together with gene expression trends in vivo, these data support early priming activation of target tissue γδ T cells during Salmonella serovar Typhimurium infection.

Innate immune system stimulants (innate adjuvants) offer complementary approaches to vaccines and antimicrobial compounds to increase host resistance to infection. The authors established fetal bovine intestinal epithelial cell (BIEC) cultures to screen natural product and synthetic compound libraries for novel mucosal adjuvants. They showed that BIECs from fetal intestine maintained an in vivo phenotype as reflected in cytokeratin expression, expression of antigens restricted to intestinal enterocytes, and induced interleukin-8 (IL-8) production. BIECs could be infected by and support replication of bovine rotavirus. A semi-high-throughput enzyme-linked immunosorbent assay-based assay that measured IL-8 production by BIECs was established and used to screen commercially available natural compounds for novel adjuvant activity. Five novel hits were identified, demonstrating the utility of the assay for selecting and screening new epithelial cell adjuvants. Although the identified compounds had not previously been shown to induce IL-8 production in epithelial cells, other known functions for 3 of the 5 were consistent with this activity. Statistical analysis of the throughput data demonstrated that the assay is adaptable to a high-throughput format for screening both synthetic and natural product derived compound libraries. (Journal of Biomolecular Screening 2006:664-671)

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We have begun to elucidate the role of γδ T cells in innate immunity. Purified human and bovine γδ T cells display a subtle activation, akin to priming, in response to a wide variety of pathogen associated molecular patterns (PAMPs) such as lipopolysaccharide and peptidoglycan. A primed γδ T cell displays an enhanced response to downstream secondary signals compared to resting cells, but is not overtly activated. The signature response of a primed γδ T cell include increases in Mip1α, GM-CSF, and IL-2Rα gene and protein expression, that renders them more sensitive to IL-2. Priming is distinct from overt activation by known TCR agonists in that upregulation of IFNγ and TNFα, the signature of an activated γδ T cell, are rarely detected. Priming has also been detected in vivo in γδ, but not αβ, T cells derived from the gut mucosa of Salmonella infected calves. In an effort to manipulate γδ T cells to provide an innate protective response, we have identified compounds and herbal products that mimic the priming activation of PAMPs on γδ T cells. Treatment of bovine calves with one of the plant extracts protects against Salmonella-induced enterocolitis. γδ T cell priming may be a critical step in innate immune protection and clearance, especially for pathogens that invade mucosal surfaces, where the majority of γδ T cells are found.