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While CD4 Th1 cells are required for resistance to intramacrophage infections, adoptive transfer of Th1 cells is insufficient to protect against Salmonella infection. Using an epitope-tagged vaccine strain of Salmonella, we found that effective protection correlated with expanded Salmonella-specific memory CD4 T cells in circulation and nonlymphoid tissues. However, naive mice that previously shared a blood supply with vaccinated partners lacked T cell memory with characteristics of tissue residence and did not acquire robust protective immunity. Using a YFP-IFN-γ reporter system, we identified Th1 cells in the liver of immunized mice that displayed markers of tissue residence, including P2X7, ARTC2, LFA-1, and CD101. Adoptive transfer of liver memory cells after ARTC2 blockade increased protection against highly virulent bacteria. Taken together, these data demonstrate that noncirculating memory Th1 cells are a vital component of immunity to Salmonella infection and should be the focus of vaccine strategies.

The development of a subunit Salmonella vaccine has been hindered by the absence of detailed information about antigenic targets of protective Salmonella-specific T and B cells. Recent studies have identified SseB as a modestly protective Ag in susceptible C57BL/6 mice, but the mechanism of protective immunity remains undefined. In this article, we report that simply combining Salmonella SseB with flagellin substantially enhances protective immunity, allowing immunized C57BL/6 mice to survive for up to 30 d following challenge with virulent bacteria. Surprisingly, the enhancing effect of flagellin did not require flagellin Ag targeting during secondary responses or recognition of flagellin by TLR5. Although coimmunization with flagellin did not affect SseB-specific Ab responses, it modestly boosted CD4 responses. In addition, protective immunity was effectively transferred in circulation to parabionts of immunized mice, demonstrating that tissue-resident memory is not required for vaccine-induced protection. Finally, protective immunity required host expression of IFN-γR but was independent of induced NO synthase expression. Taken together, these data indicate that Salmonella flagellin has unique adjuvant properties that improve SseB-mediated protective immunity provided by circulating memory.

IL-15 and the IL-15 receptor (IL-15R)[alpha] chain are essential for normal development of naive CD8 T cells, intestinal intraepithelial lymphocytes (IEL), and natural killer (NK)/NK/T cells. However, whether IL-15R[alpha] expression by these subsets is necessary for their production and which cell type needs to produce IL-15 to drive development are unknown. We analyzed the requirements for IL-15 and IL-15R[alpha] expression by bone marrow-derived or parenchymal cells for mediating lymphocyte subset development. Naive CD8 T cell development required IL-15R[alpha] expression by both bone marrow-derived and parenchymal cells, whereas memory-pheno-type CD8 T cells required IL-15R[alpha] expression only by hematopoietic cells. In contrast and surprisingly, the development of IEL subsets, particularly CD8[alpha][alpha]Thy1-V[gamma][5.sup.+] T cell antigen receptor [gamma][delta] and the CD8[alpha][alpha] Thy[1.sup.-] T cell antigen receptor [alpha][beta] IEL populations, depended completely on parenchymal cell expression of IL-15R[alpha] and IL-15 but not IL-15R[beta]. In the case of NK and NK/T cell generation and maturation, expression of IL-15 and IL-15R[alpha] by both parenchymal and hematopoietic cells was important, although the latter played the greatest role. These results demonstrated dichotomous mechanisms by which IL-15 regulated lymphoid development, interacting with distinct cell types depending on the developmental pathway.

Breast milk protects young mice from developing symptoms of asthma. The effect occurs through the induction of regulatory T cells after ingestion of allergen and TGF-[beta] in breast milk (pages [...]

Abstract Background The mechanism(s) responsible for the reduced risk of allergic disease in breastfed infants are not fully understood. Using an established murine model of asthma, we demonstrated previously that resistance to allergic airway disease transmitted from allergic mothers to breastfed offspring requires maternal B cell-derived factors. Objective The aim of this study was to investigate the role of offspring neonatal Fc receptor for IgG uptake by intestinal epithelial cells (FcRn) in this breast milk transferred protection from allergy. Methods Allergic airway disease was induced during pregnancy in C57BL/6 female mice. These allergic mothers foster nursed naive FcRn+/- or FcRn-/- progeny born to FcRn+/- females that were mated to C57BL/6J-FcRn-/- male mice. In offspring deficient in FcRn, we expected reduced levels of systemic allergen-specific IgG1, a consequence of decreased absorption of maternal IgG from the lumen of the neonatal gastrointestinal tract. Using this model, we were able to investigate how breast milk IgG affected offspring responses to allergic sensitization. Results Levels of maternal antibodies absorbed from the breast milk of allergic foster mothers were determined in weanling FcRn-sufficient or -deficient mice. Maternal transmission of allergen-specific IgG1 to breastfed FcRn-/- offspring was at levels 103-104 lower than observed in FcRn+/- or FcRn+/+ mice. Five weeks after weaning, when offspring were 8 wk old, mice were sensitized and challenged to evaluate their susceptibility to develop allergic airway disease. Protection, indicated by reduced parameters of disease (allergen-specific IgE in serum, eosinophilic inflammation in the airways and lung) were evident in FcRn-sufficient mice nursed as neonates by allergic mothers. In contrast, FcRn-deficient mice breastfed by the same mothers acquired limited, if any, protection from development of allergen-specific IgE and associated pathology. Conclusions FcRn expression was a major factor in determining how breastfed offspring of allergic mothers acquired levels of systemic allergen-specific IgG1 sufficient to inhibit allergic sensitization in this model.