The functions of mucosal T cells in containing the indigenous commensal flora of the intestine.

There is an immense load of non-pathogenic commensal bacteria in the distal small intestine and the colon of mammals. The physical barrier that prevents penetration (translocation) of these organisms into the body is a simple epithelium comprised of the single enterocyte/colonocyte cell layer with its overlying mucus. In this review, we discuss the roles of intestinal T cells in initiating and regulating innate and adaptive mucosal immune responses of the mucosal immune system that avoid or limit penetration of the commensal intestinal bacteria.

CD4+ T-cell-epitope escape mutant virus selected in vivo.

Mutations in viral genomes that affect T-cell-receptor recognition by CD8+ cytotoxic T lymphocytes have been shown to allow viral evasion from immune surveillance during persistent viral infections. Although CD4+ T-helper cells are crucially involved in the maintenance of effective cytotoxic T-lymphocyte and neutralizing-antibody responses, their role in viral clearance and therefore in imposing similar selective pressures on the virus is unclear. We show here that transgenic virus-specific CD4+ Tcells, transferred into mice persistently infected with lymphocytic choriomeningitis virus, select for T-helper epitope mutant viruses that are not recognized. Together with the observed antigenic variation of the same T-helper epitope during polyclonal CD4+ T-cell responses in infected pore-forming protein-deficient C57BL/6 mice, this finding indicates that viral escape from CD4+ T lymphocytes is a possible mechanism of virus persistence.

MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway,.

Induction of MHC class I genes in neurons of the central nervous system requires signals by pro-inflammatory cytokines, in particular IFN-gamma, and the blockade of electric activity, which is known to suppress induction of MHC related genes in a highly ordered, but unusual fashion [1], [2]. The present experiments explore the immunological function of neuronal MHC class I antigens expressed under permissive conditions. MHC class I proteins were induced in electrically silenced murine hippocampal neurons by treatment with the sodium channel blocker tetrodotoxin and recombinant IFN-gamma, conditions which also resulted in the induction of Fas molecules. The MHC class I positive neurons were challenged with CD8+ cytotoxic T lymphocytes (CTL) specific for the H2-Db binding peptide GP33, a dominant epitope of the lymphocytic choriomeningitis virus envelope glycoprotein, or with alloreactive CTL. Single primed neurons, attacked by GP33-specific CTL, were continuously monitored for changes in intracellular calcium ([Ca2+]i), an indicator of cytotoxic damage. MHC class I-induced neurons pulsed with the GP33 peptide, but not a control peptide, showed a gradual and sustained increase in [Ca2+]i within 3 h following attack by GP33-specific CTL, while in astrocytes [Ca2+]i elevation was rapid. The slow course of the neuronal response was consistent with a delayed apoptotic killing mechanism rather than rapid granule-mediated plasma membrane lysis. Indeed, the attacked neurons bound annexin V, indicating membrane alterations preceding apoptotic cell death. In further support of apoptotic cell death, this sustained increase of [Ca2+]i levels was also observed following attack by perforin-deficient CTL, but was not detected in neurons derived from mutant lpr mice, which lack functional Fas molecules.

CpG-containing oligonucleotides are efficient adjuvants for induction of protective antiviral immune responses with T-cell peptide vaccines.

Synthetic nonmethylated oligonucleotides containing CpG dinucleotides (CpG-ODNs) have been shown to exhibit immunostimulatory activity. CpG-ODNs have the capacity to directly activate B cells, macrophages, and dendritic cells, and we show here that this is reflected by cell surface binding of oligonucleotides to these cell subsets. However, T cells are not directly activated by CpG-ODNs, which correlates with the failure to bind to the T-cell surface. Efficient competition for CpG-induced B-cell activation by non-CpG-containing oligonucleotides suggests that oligonucleotides might bind to an as yet undefined sequence-nonspecific receptor prior to cellular activation. Induction of protective T-cell responses against challenge infection with lymphocytic choriomeningitis virus (LCMV) or with recombinant vaccinia virus expressing the LCMV glycoprotein was achieved by immunizing mice with the immunodominant major histocompatibility complex class I-binding LCMV glycoprotein-derived peptide gp33 together with CpG-ODNs. In these experiments, B cells, potentially serving as CpG-ODN-activated antigen-presenting cells (APCs), were not required for induction of protective immunity since CpG-ODN-gp33-immunized B-cell-deficient mice were equally protected against challenge infection with both viruses. This finding suggested that macrophages and/or dendritic cells were sufficiently activated in vivo by CpG-ODNs to serve as potent APCs for the induction of naive T cells. Furthermore, treatment with CpG-ODN alone induced protection against infection with Listeria monocytogenes via antigen-independent activation of macrophages. These data suggest that CpG activation of macrophages and dendritic cells may provide a critical step in CpG-ODN adjuvant activity.