Ag presentation to CD4 T cells can be mediated by a number of cell types depending on the anatomical site in which Ag is first encountered. For blood borne Ags, cells localized in situ in the spleen should be major players. There is now much evidence that B cell Ag presentation may be particularly important in the priming of memory T cells. The majority of NK cells are also localized the spleen. Inasmuch as we have previously shown that NK cells can modulate various aspects of B cell differentiation, we entertained the possibility that NK cells can also influence Ag presentation by B cells. By specific depletion of NK cells before immunization, we show herein that NK cells play an important role in modulating the ability of B cells to process and present Ag to T cells. These effects are particularly important in the generation of memory T cells. The findings are further substantiated by in vitro experiments showing that the enhancement does not require IFN-gamma but is mediated by direct cell-cell interaction. These results show, for the first time, that the rapid activation of a component of the innate response can even exert effects on the Ag-specific memory response.
"Activation in mice was detected only from NK cells. Interestingly, recent studies have expanded the role of NK cells from their traditional importance as part of the innate immune response to include their influence on adaptive immune responses and the establishment of long-term memory  (reviewed in , ). The present data suggest that 5mer4 can activate NK cells resulting in an enhance adaptive immune responses as observed by increased T and B-cells responses and survival following challenge 28 days post-treatment. "
[Show abstract][Hide abstract] ABSTRACT: Certain short peptides do not occur in humans and are rare or non-existent in the universal proteome. Antigens that contain rare amino acid sequences are in general highly immunogenic and may activate different arms of the immune system. We first generated a list of rare, semi-common, and common 5-mer peptides using bioinformatics tools to analyze the UniProtKB database. Experimental observations indicated that rare and semi-common 5-mers generated stronger cellular responses in comparison with common-occurring sequences. We hypothesized that the biological process responsible for this enhanced immunogenicity could be used to positively modulate immune responses with potential application for vaccine development. Initially, twelve rare 5-mers, 9-mers, and 13-mers were incorporated in frame at the end of an H5N1 hemagglutinin (HA) antigen and expressed from a DNA vaccine. The presence of some 5-mer peptides induced improved immune responses. Adding one 5-mer peptide exogenously also offered improved clinical outcome and/or survival against a lethal H5N1 or H1N1 influenza virus challenge in BALB/c mice and ferrets, respectively. Interestingly, enhanced anti-HBsAg antibody production by up to 25-fold in combination with a commercial Hepatitis B vaccine (Engerix-B, GSK) was also observed in BALB/c mice. Mechanistically, NK cell activation and dependency was observed with enhancing peptides ex vivo and in NK-depleted mice. Overall, the data suggest that rare or non-existent oligopeptides can be developed as immunomodulators and supports the further evaluation of some 5-mer peptides as potential vaccine adjuvants.
PLoS ONE 08/2012; 7(8):e43802. DOI:10.1371/journal.pone.0043802 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The major role of NK cells has traditionally been assigned to their cytotoxic activity both against tumor cells and against virus-infected cells. Only recently has there been greater appreciation for their more diverse functions. The interaction between NK and B cells is unique in that NK cells have not been reported to kill B cells, allowing, therefore productive interactions between the two cell types. In this review we have focused on the ability of NK cells to influence the two major functions of B cells, their ability to secrete antibodies and to present antigen to T cells. This review provides the definitive evidence obtained from in vitro experiments that NK and B cells can interact productively in both directions. In addition, much progress has been made toward identification of the receptor–ligand pairs required for the interaction. This review also points out that whereas there is evidence for similar interactions to occur in vivo, unraveling the mechanisms by which this occurs is more challenging due to the many players involved. For this same reason we have focused the review in the mouse system which is more amenable to in vivo manipulation. We realize that much insights derived from work with human cells should be informative, but complete correlation with findings between the two system is beyond the scope of this review.
[Show abstract][Hide abstract] ABSTRACT: There is growing evidence incriminating B lymphocytes in the pathogenesis of graft-versus-host disease (GVHD). Better understanding of the role of B lymphocytes has uncovered new therapeutic approaches, such as CD20 blockade, which appear to be improving outcomes in allogeneic hematopoietic cell transplant recipients. Administration of the chimeric murine/human anti-CD20 monoclonal antibody, rituximab, prior to hematopoietic cell allografting or as part of preparative regimens appears to reduce treatment-related mortality and to improve posttransplant outcomes mainly by decreasing the incidence and severity of acute GVHD. This beneficial effect of rituximab has not had an impact, to the same extent on the incidence of chronic GVHD, which remains a significant cause of morbidity and mortality following hematopoietic cell allografting. Alternatively, rituximab has been shown to be effective for treatment of cGVHD, but data is limited because of the lack of randomized controlled clinical trials and the small sample size in most of the published series. Incorporation of rituximab into the therapeutic armamentarium of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder has clearly improved the overall prognosis of this dreadful disease. This review highlights the evolving role of CD20 blockade in allogeneic hematopoietic cell transplantation and the need to continue to refine B cell depletion strategies in this setting.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2010; 16(10):1347-54. DOI:10.1016/j.bbmt.2010.01.005 · 3.40 Impact Factor
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