Inducible deletion of CD28 prior to secondary nippostrongylus brasiliensis infection impairs worm expulsion and recall of protective memory CD4 (+) T cell responses

IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28−/− mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28−/loxCre+/−+TM) to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28−/− mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28−/loxCre+/− mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28−/− mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5+ TFH cell population. Furthermore, total number of CD4+ T cells and B220+ B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28−/− mice and tamoxifen treated CD28−/loxCre+/− mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4+ T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28−/loxCre+/− mice. Therefore, it can be concluded that CD28 costimulation is essential for conferring host protection during secondary N. brasiliensis infection

Mechanisms of antitumor and immune-enhancing activities of MUC1/sec, a secreted form of mucin-1

Mucin 1 (MUC1) is a polymorphic type 1 transmembrane protein found on the apical surface of normal cells lining the lumen of ducts and glands. Mucins are thought to provide mucosal protection from environmental exposures and carcinogens. An altered form of the MUC1 glycoprotein, which is hypoglycosylated, is expressed in several types of human cancers. In our laboratory, we have found that transfection of a murine mammary tumor cell line with a human secreted isoform of MUC1 rendered these DA-3 cells (DA-3/sec) incapable of growing in intact BALB/c mice. In contrast, implantation of DA-3 cells transfected with the human transmembrane isoform of MUC1 (DA-3/TM), resulted in tumor formation and ultimately death of the animals, similar to the DA-3 parental line. Importantly, inoculation of the DA-3/sec cells in immunodeficient nude mice resulted in tumor formation, indicating that the MUC1/sec molecule’s antitumor activity is immunologically controlled. In this review, we summarize the studies we have performed to elucidate possible mechanisms for the immune-mediated antitumor effect of MUC1/sec and/or a unique peptide present in this mucin. Understanding these mechanisms may provide new immunotherapeutic approaches that could be used to target different types of cancer