Antigenic Sequences of Poliovirus Recognized by T Cells: Serotype-Specific Epitopes on VP1 and VP3 and Cross-Reactive Epitopes on VP4 Defined by Using CD4+ T-Cell Clones

A panel of poliovirus-specific murine CD4+ T-cell clones has been established from both BALB/c (H-2d) and CBA (H-2k) mice immunized with Sabin vaccine strains of poliovirus serotype 1, 2, or 3. T-cell clones were found to be either serotype specific or cross-reactive between two or all three serotypes. Specificity analysis against purified poliovirus proteins demonstrated that T-cell clones recognized determinants on the surface capsid proteins VP1, VP2, and VP3 and the internal capsid protein VP4. Panels of overlapping synthetic peptides were used to identify eight distinct T-cell epitopes. One type 3-specific T-cell clone recognized an epitope within amino acids 257 and 264 of VP1. Three T-cell epitopes corresponding to residues 14 to 28, 189 to 203, and 196 to 210 were identified on VP3 of poliovirus type 2. The remaining four T-cell epitopes were mapped to an immunodominant region of VP4, encompassed within residues 6 and 35 and recognized by both H-2Z and H-2k mice. The epitopes on VP4 were conserved between serotypes, and this may account for the predominantly cross-reactive poliovirus-specific T-cell response observed with polyclonal T-cell populations. In contrast, T-cell clones that recognize epitopes on VP1 or VP3 were largely serotype specific; single or multiple amino acid substitutions were found to be critical for T-cell recognition

A crucial role for interleukin (IL)-1 in the induction of IL-17–producing T cells that mediate autoimmune encephalomyelitis

It was recently demonstrated that interleukin (IL)-23–driven IL-17–producing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction of antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type I–deficient (IL-1RI−/−) mice. Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI−/− compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different. However, EAE was induced in IL-1RI−/− mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23 alone did not induce IL-17 production by T cells from IL-1RI−/− mice, and IL-23–induced IL-17 production was substantially enhanced by IL-1α or IL-1β, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor κB, and novel protein kinase C isoforms in IL-1– and IL-23–mediated IL-17 production. Tumor necrosis factor α also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE

Caspase-11 regulates the tumour suppressor function of STAT1 in a murine model of colitis-associated carcinogenesis

Murine inflammatory caspase-11 has an important role in intestinal epithelial inflammation and barrier function. Activation of the non-canonical inflammasome, mediated by caspase-11, serves as a regulatory pathway for the production of the proinflammatory cytokines IL-1β and IL-18, and has a key role in pyroptotic cell death. We have previously demonstrated a protective role for caspase-11 during dextran sulphate sodium (DSS)-induced colitis, however the importance of caspase-11 during colorectal tumour development remains unclear. Here, we show that Casp11−/− mice are highly susceptible to the azoxymethane (AOM)-DSS model of colitis-associated cancer (CAC), compared to their wild type (WT) littermates. We show that deficient IL-18 production occurs at initial inflammation stages of disease, and that IL-1β production is more significantly impaired in Casp11−/− colons during established CAC. We identify defective STAT1 activation in Casp11−/− colons during disease progression, and show that IL-1β signalling induces caspase-11 expression and STAT1 activation in primary murine macrophages and intestinal epithelial cells. These findings uncover an anti-tumour role for the caspase-11 and the non-canonical inflammasome during CAC, and suggest a critical role for caspase-11, linking IL-1β and STAT1 signalling pathways

HIV p24-Specific Helper T Cell Clones From Immunised Primates Recognize Highly Conserved Regions of HIV-l

We have investigated Th cell recognition of the HIV core protein p24 by using CD4+ T cell clones derived from cynomolgus macaques immunized with hybrid HIV p24:Ty virus-like particles (VLP). T cell lines from two immunized animals responded to p24:Ty-VLP, control Ty-VLP, purified p24, and whole inactivated HIV, indicating the presence of T cells specific for p24 as well as the Ty carrier protein. The HIV determinants recognized by the T cell lines were identified by using a series of overlapping peptides synthesized according to the sequence of p24. Both T cell lines recognized peptide 11 (amino acids 235-249) and peptide 14 (amino acids 265- 279). In addition, one T cell line also responded to peptide 9 (amino acids 215-229). Definitive identification of two T cell epitopes on p24 was confirmed at the clonal level: from a total of four T cell clones generated from one of the T cell lines, two respond specifically to peptide 11 and two to peptide 14. The T cell clones were CD4' and MHC class 11-restricted and secreted IL-2 in response to stimulation with purified p24, inactivated HIV or a single synthetic peptide. The specificityof the Th clones for variant peptides demonstrated cross-reactivity with two simian immunodeficiency virus isolates, but only limited responses to HIV-2 sequences. However, the Th cell epitopes identified on p24 are highly conserved between 12 HIV-1 isolates and were recognized by both of the immunized primates. These sequences may therefore be useful for priming a broadly reactive immune response to HIV-1

A population of proinflammatory T cells coexpresses αβ and γδ T cell receptors in mice and humans

T cells are classically recognized as distinct subsets that express αβ or γδ TCRs. We identify a novel population of T cells that coexpress αβ and γδ TCRs in mice and humans. These hybrid αβ-γδ T cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αβ TCR–mediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRδ+ cells in lymphoid organs. They expressed high levels of IL-1R1 and IL-23R and secreted IFN-γ, IL-17, and GM-CSF in response to canonically restricted peptide antigens or stimulation with IL-1β and IL-23. Hybrid αβ-γδ T cells were transcriptomically distinct from conventional γδ T cells and displayed a hyperinflammatory phenotype enriched for chemokine receptors and homing molecules that facilitate migration to sites of inflammation. These proinflammatory T cells promoted bacterial clearance after infection with Staphylococcus aureus and, by licensing encephalitogenic Th17 cells, played a key role in the development of autoimmune disease in the central nervous system

Next-Generation Pertussis Vaccines Based on the Induction of Protective T Cells in the Respiratory Tract

Immunization with current acellular pertussis (aP) vaccines protects against severe pertussis, but immunity wanes rapidly after vaccination and these vaccines do not prevent nasal colonization with Bordetella pertussis. Studies in mouse and baboon models have demonstrated that Th1 and Th17 responses are integral to protective immunity induced by previous infection with B. pertussis and immunization with whole cell pertussis (wP) vaccines. Mucosal Th17 cells, IL-17 and secretory IgA (sIgA) are particularly important in generating sustained sterilizing immunity in the nasal cavity. Current aP vaccines induce potent IgG and Th2-skewed T cell responses but are less effective at generating Th1 and Th17 responses and fail to prime respiratory tissue-resident memory T (TRM) cells, that maintain long-term immunity at mucosal sites. In contrast, a live attenuated pertussis vaccine, pertussis outer membrane vesicle (OMV) vaccines or aP vaccines formulated with novel adjuvants do induce cellular immune responses in the respiratory tract, especially when delivered by the intranasal route. An increased understanding of the mechanisms of sustained protective immunity, especially the role of respiratory TRM cells, will facilitate the development of next generation pertussis vaccines that not only protect against pertussis disease, but prevent nasal colonization and transmission of B. pertussis

Antigenic Sequences of Poliovirus Recognized by T Cells: Serotype-Specific Epitopes on VP1 and VP3 and Cross-Reactive Epitopes on VP4 Defined by Using CD4+ T-Cell Clones

A panel of poliovirus-specific murine CD4+ T-cell clones has been established from both BALB/c (H-2d) and CBA (H-2k) mice immunized with Sabin vaccine strains of poliovirus serotype 1, 2, or 3. T-cell clones were found to be either serotype specific or cross-reactive between two or all three serotypes. Specificity analysis against purified poliovirus proteins demonstrated that T-cell clones recognized determinants on the surface capsid proteins VP1, VP2, and VP3 and the internal capsid protein VP4. Panels of overlapping synthetic peptides were used to identify eight distinct T-cell epitopes. One type 3-specific T-cell clone recognized an epitope within amino acids 257 and 264 of VP1. Three T-cell epitopes corresponding to residues 14 to 28, 189 to 203, and 196 to 210 were identified on VP3 of poliovirus type 2. The remaining four T-cell epitopes were mapped to an immunodominant region of VP4, encompassed within residues 6 and 35 and recognized by both H-2Z and H-2k mice. The epitopes on VP4 were conserved between serotypes, and this may account for the predominantly cross-reactive poliovirus-specific T-cell response observed with polyclonal T-cell populations. In contrast, T-cell clones that recognize epitopes on VP1 or VP3 were largely serotype specific; single or multiple amino acid substitutions were found to be critical for T-cell recognition