INFLUENCE OF INTESTINAL SURFACTANT LIKE PARTICLES ON DIFFERENTIAL ACTIVATION OF SECONDARY SIGNALING MOLECULES DURING SALMONELLA TYPHIMURIUM INFECTION

Interaction between the enteric pathogen Salmonella typhimurium and the luminal surface of the intestine provoke an acute inflammatory response mediated in part by various inflammatory molecules. Surfactant-like particles (SLP) are known to cover the surface of the intestinal epithelium, act as lubricants and/or as a vehicle to deliver digestive enzymes to the luminal fluid. Recently we have shown that SLP plays an important protective role during microbial insult. The data suggested that SLP-induced diet prevents the damage of intestinal villi caused by S. typhimurium infection. The present study was designed to assess the role of SLP on secondary signaling molecules during S. typhimurium infection. The Peyer's patch, intraepithelial and lamina propria mononuclear cells were analyzed under various conditions for secondary signaling molecules, including calcium, inositol triphosphate and protein kinase C. SLP-induced diet along with infection showed significant variation in these secondary signaling molecules, particularly in Peyer's patches, as compared to infection group alone. In addition, the cells isolated from the infected group upon incubation in vitro with SLP also showed a considerable variation of these molecules. These results suggested an important influence of SLP on secondary signaling molecules and, in turn, could be important in overall immune modulation during infection. Salmonella are known to cause disease in humans, animals and birds worldwide. Over 1.4 million cases of salmonellosis (gastroenteritis) per year occur in the U.S.A. and other industrialized countries. Countries with poor sanitation have a much higher incidence of salmonellosis. The disruption of epithelial barrier integrity by Salmonella has pathological consequences. Intestinal epithelium secretes surfactant-like particles (SLP); these particles have the ability to cover the surface of the cell in the intestinal lumen. They are known to have ability in binding of uropathogenic Escherichia coli and in protecting the disruption of intestinal villi. The present study provides further evidence for its role in regulating secondary signaling molecules and overall immune response. SLP induced by dietary fat enhanced the resistance to intestinal infections, as it possibly decreases the colonization and translocation of S. typhimurium . The SLP and microbe interaction may thus represent a delicate balance between symbiosis and pathogenesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79314/1/j.1745-4565.2010.00219.x.pd

MHC class IIâ expressing thymocytes suppress invariant NKT cell development

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141892/1/imcb200878.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141892/2/imcb200878-sup-0001.pd

PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity

PIM kinase family members play a crucial role in promoting cell survival and proliferation via phosphorylation of their target substrates. In this study, we investigated the role of the PIM kinases with respect to T cell responses in transplantation and tumor immunity. We found that the PIM-2 isoform negatively regulated T cell responses to alloantigen, in contrast to the PIM-1 and PIM-3 isoforms, which acted as positive regulators. T cells deficient in PIM-2 demonstrated increased T cell differentiation toward Th1 subset, proliferation, and migration to target organs after allogeneic bone marrow transplantation, resulting in dramatically accelerated graft-versus-host disease (GVHD) severity. Restoration of PIM-2 expression markedly attenuated the pathogenicity of PIM-2-deficient T cells to induce GVHD. On the other hand, mice deficient in PIM-2 readily rejected syngeneic tumor, which was primarily dependent on CD8(+) T cells. Furthermore, silencing PIM-2 in polyclonal or antigen-specific CD8(+) T cells substantially enhanced their antitumor response in adoptive T cell immunotherapy. We conclude that PIM-2 kinase plays a prominent role in suppressing T cell responses, and provide a strong rationale to target PIM-2 for cancer immunotherapy.Biostatistics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]; University of Arizona Cancer Center [P30 CA023074]; NIH [R01CA173200, R01 CA169116, R01 AI118305, R01 HL137373, R21 CA192202]; DOD [W81XWH-12-1-0560]; SmartState Endowment in Cancer Stem Cell Biology & Therapy ProgramThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

A single strain of Bacteroides fragilis protects gut integrity and reduces GVHD

Graft-versus-host disease (GVHD) is a pathological process caused by an exaggerated donor lymphocyte response to host antigens after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells undergo extensive clonal expansion and differentiation, which culminate in damage to recipient target organs. Damage to the gastrointestinal tract is a main contributor to morbidity and mortality. The loss of diversity among intestinal bacteria caused by pretransplant conditioning regimens leads to an outgrowth of opportunistic pathogens and exacerbated GVHD after allo-HCT. Using murine models of allo-HCT, we found that an increase of Bacteroides in the intestinal microbiota of the recipients was associated with reduced GVHD in mice given fecal microbial transplantation. Administration of Bacteroides fragilis through oral gavage increased gut microbiota diversity and beneficial commensal bacteria and significantly ameliorated acute and chronic GVHD development. Preservation of gut integrity following B. fragilis exposure was likely attributed to increased short chain fatty acids, IL-22, and regulatory T cells, which in turn improved gut tight junction integrity and reduced inflammatory cytokine production of pathogenic T cells. The current study provides a proof of concept that a single strain of commensal bacteria can be a safe and effective means to protect gut integrity and ameliorate GVHD after allo-HCT