T cell activation by dendritic cells (DCs) is critical to the initiation of adaptive immune responses and protection against pathogens. Here, we demonstrate that a specialized DC subset in Peyer's patches (PPs) mediates the rapid activation of pathogen specific T cells. This DC subset is characterized by the expression of the chemokine receptor CCR6 and is found only in PPs. CCR6(+) DCs were recruited into the dome regions of PPs upon invasion of the follicle associated epithelium (FAE) by an enteric pathogen and were responsible for the rapid local activation of pathogen-specific T cells. CCR6-deficient DCs were unable to respond to bacterial invasion of PPs and failed to initiate T cell activation, resulting in reduced defense against oral infection. Thus, CCR6-dependent regulation of DCs is responsible for localized T cell dependent defense against entero-invasive pathogens.

IntroductionTumor-induced immune suppression is a fundamental problem in cancer biology and immunotherapy. COX metabolites act as tumor promoters when overproduced (1-3), and recent studies have demonstrated that the COX metabolite prostaglandin E 2 (PGE 2 ) exhibits potent immunosuppressive effects, orchestrating an imbalance between type 1 and type 2 cytokines (4-6). PGE 2 mediates its effects, in part, through G proteincoupled PGE receptors, designated EP1, EP2, EP3, and EP4. Differential expression of these EP receptors mediate the diverse, and often antagonistic, effects of PGE 2 and its analogues on a variety of cell types (7-9). The EP2 receptor regulates the activation and differentiation of mouse B lymphocytes (10), modulates T cell development (11-12), and regulates macrophage cytokine release (13) and postsurgery immune responses (14). The EP2 receptor also plays a key role in the differentiation of macrophage-like osteoclast cells as well as the functional response of osteoclasts to PGE 2 (15). Importantly, PGE 2 has been shown to be a key modulator of DC function, altering cytokine production as well as the I-A d class II cell surface marker (16)(17). Despite data describing the production of PGE 2 by tumors and the expression of the EP2 receptor in specific immune populations, the role of the EP2 receptor in modulation of the host immune response to tumors remains uncharacterized.Previous studies show that COX-2 and PGE 2 can play important roles in tumor angiogenesis (3,18,19). Recent publications show that in Apc ∆716 mice, a mouse model for human familial adenomatous polyposis, homozygous deletion of the gene encoding EP2 decreases the number and size of intestinal polyps through inhibition of tumor angiogenesis (19,20). In this study we determined the role of the EP2 receptor in host-tumor interactions. Unlike the results observed in the Apc ∆716 model, we observed no effect of the disruption of the EP2 receptor on tumor angiogenesis. We then examined the role of the EP2 receptor in T cell function, as well as DC differentiation, and functional responses to tumor challenge. Our data demonstrate an important role for the EP2

IntroductionTumor-induced immune suppression is a fundamental problem in cancer biology and immunotherapy. COX metabolites act as tumor promoters when overproduced (1-3), and recent studies have demonstrated that the COX metabolite prostaglandin E 2 (PGE 2 ) exhibits potent immunosuppressive effects, orchestrating an imbalance between type 1 and type 2 cytokines (4-6). PGE 2 mediates its effects, in part, through G proteincoupled PGE receptors, designated EP1, EP2, EP3, and EP4. Differential expression of these EP receptors mediate the diverse, and often antagonistic, effects of PGE 2 and its analogues on a variety of cell types (7-9). The EP2 receptor regulates the activation and differentiation of mouse B lymphocytes (10), modulates T cell development (11-12), and regulates macrophage cytokine release (13) and postsurgery immune responses (14). The EP2 receptor also plays a key role in the differentiation of macrophage-like osteoclast cells as well as the functional response of osteoclasts to PGE 2 (15). Importantly, PGE 2 has been shown to be a key modulator of DC function, altering cytokine production as well as the I-A d class II cell surface marker (16)(17). Despite data describing the production of PGE 2 by tumors and the expression of the EP2 receptor in specific immune populations, the role of the EP2 receptor in modulation of the host immune response to tumors remains uncharacterized.Previous studies show that COX-2 and PGE 2 can play important roles in tumor angiogenesis (3,18,19). Recent publications show that in Apc ∆716 mice, a mouse model for human familial adenomatous polyposis, homozygous deletion of the gene encoding EP2 decreases the number and size of intestinal polyps through inhibition of tumor angiogenesis (19,20). In this study we determined the role of the EP2 receptor in host-tumor interactions. Unlike the results observed in the Apc ∆716 model, we observed no effect of the disruption of the EP2 receptor on tumor angiogenesis. We then examined the role of the EP2 receptor in T cell function, as well as DC differentiation, and functional responses to tumor challenge. Our data demonstrate an important role for the EP2

IL-18 induces inflammation resulting in either enhanced protection from pathogens or exacerbation of autoimmunity, and T cells are profoundly activated during these responses. How IL-18 influences T cell activation is unknown, but this study in mice shows that IL-18 boosted Ag-specific T cell clonal expansion of effector T cells and induced a subpopulation of IFN-γ superproducing T cells. Commitment to IFN-γ production through IL-18 was independent of NK cells and IL-12 but dependent on host-derived IFN-γ. To determine how expansion of these effectors occurred, IL-18 was shown to induce OX40L on dendritic cells, whereas peptide stimulation induced CD134 (OX40) on specific T cells. CD134 blockade inhibited T cell effector expansion thereby reducing the number of IFN-γ superproducers by 12-fold. Thus, independent of IL-12, IL-18 impacts T cell immunity throughout lymphoid and nonlymphoid tissue by bridging the innate and adaptive arms of the immune system through IFN-γ and the CD134 costimulatory pathway.

Minor histocompatibility (H) Ag disparities result in graft-vs-host disease and chronic solid allograft rejection in MHC-identical donor-recipient combinations. Minor H Ags are self protein-derived peptides presented by MHC class I molecules. Most arise as a consequence of allelic variation in the bound peptide (p) that results in TCR recognizing the p/MHC as foreign. We used a combinational peptide screening approach to identify the immune dominant H2Kb-restricted epitope defining the mouse H4b minor H Ag. H4b is a consequence of a P3 threonine to isoleucine change in the MHC-bound peptide derived from epithelial membrane protein-3. This allelic variation also leads to phosphorylation of the H4b but not the H4a epitope. Further, ex vivo CD8+ T lymphocytes bind phosphorylated Ag tetramers with high efficiency. Although we document the above process in the minor H Ag system, posttranslational modifications made possible by subtle amino acid changes could also contribute to immunogenicity and immune dominance in tumor immunotherapeutic settings.