Type I interferon supports primary CD8+ T-cell responses to peptide-pulsed dendritic cells in the absence of CD4+ T-cell help

Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute for Biomedical Sciences, University of Rochester Medical Center, Rochester, NY 14642-8609, USA.
Immunology (Impact Factor: 3.8). 04/2011; 132(4):549-58. DOI: 10.1111/j.1365-2567.2010.03400.x
Source: PubMed

ABSTRACT CD8(+) T-cell responses to non-pathogen, cell-associated antigens such as minor alloantigens or peptide-pulsed dendritic cells (DC) are usually strongly dependent on help from CD4(+) T cells. However, some studies have described help-independent primary CD8(+) T-cell responses to cell-associated antigens, using immunization strategies likely to trigger natural killer (NK) cell activation and inflammatory cytokine production. We asked whether NK cell activation by MHC I-deficient cells, or administration of inflammatory cytokines, could support CD4(+) T-cell help-independent primary responses to peptide-pulsed DC. Injection of MHC I-deficient cells cross-primed CD8(+) T-cell responses to the protein antigen ovalbumin (OVA) and the male antigen HY, but did not stimulate CD8(+) T-cell responses in CD4-depleted mice; hence NK cell stimulation by MHC I-deficient cells did not replace CD4(+) T-cell help in our experiments. Dendritic cells cultured with tumour necrosis factor-α (TNF-α) or type I interferon-α (IFN-α) also failed to prime CD8(+) T-cell responses in the absence of help. Injection of TNF-α increased lymph node cellularity, but did not generate help-independent CD8(+) T-cell responses. In contrast, CD4-depleted mice injected with IFN-α made substantial primary CD8(+) T-cell responses to peptide-pulsed DC. Mice deficient for the type I IFN receptor (IFNR1) made CD8(+) T-cell responses to IFNR1-deficient, peptide-pulsed DC; hence IFN-α does not appear to be a downstream mediator of CD4(+) T-cell help. We suggest that primary CD8(+) T-cell responses will become help-independent whenever endogenous IFN-α secretion is stimulated by tissue damage, infection, or autoimmune disease.

9 Reads
  • Journal of leukocyte biology 06/2012; 91(6):845-8. DOI:10.1189/jlb.1211650 · 4.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Evaluation of: Kawaguchi S, Tsukahara T, Ida K et al. SYT-SSX breakpoint peptide vaccines in patients with synovial sarcoma: a study from the Japanese Musculoskeletal Oncology Group. Cancer Sci. 103(9), 1625-1630 (2012). The identification of genetic translocations as key tumor-initiating events has led to the development of novel antigen-specific vaccines targeting these tumor-specific breakpoint regions. Previous studies have evaluated vaccines targeting the breakpoints in the BCR-ABL translocation in patients with chronic myelogenous leukemia and EWS-FLI1 in patients with Ewing sarcoma. In the article under evaluation, the authors evaluated a peptide vaccine targeting the breakpoint in the SYT-SSX translocation, the genetic translocation essentially pathognomonic for synovial sarcoma. This is the second small clinical trial reported by this group using HLA-A24-binding peptides as vaccine antigens. In this four-arm trial, using a native or HLA-A24-optimized SYT-SSX peptide with or without adjuvant plus IFN-α, they immunized patients with metastatic synovial sarcoma. Immune responses were evaluated by delayed-type hypersensitivity testing and tetramer analysis. No robust evidence of immune response to the target epitope was detected. Some patients treated with peptide in adjuvant plus IFN-α had stable disease. These results suggest that future similar studies might best evaluate patients with a lower burden of disease, consider alternative immunization approaches to the SYT-SSX target antigen and consider the efficacy of IFN-α alone for the treatment of synovial sarcoma.
    Expert Review of Vaccines 12/2012; 11(12):1401-4. DOI:10.1586/erv.12.122 · 4.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding and identifying new ways of mounting an effective CD8(+) T cell immune response is important for eliminating infectious pathogens. Although upregulated programmed death-1 (PD1) in chronic infections (such as HIV-1 and tuberculosis) impedes T cell responses, blocking this PD1/PD-L pathway could functionally rescue the "exhausted" T cells. However, there exists a number of PD1 spliced variants with unknown biological function. Here, we identified a new isoform of human PD1 (Δ42PD1) that contains a 42-nucleotide in-frame deletion located at exon 2 domain found expressed in peripheral blood mononuclear cells (PBMCs). Δ42PD1 appears to function distinctly from PD1, as it does not engage PD-L1/PD-L2 but its recombinant form could induce proinflammatory cytokines. We utilized Δ42PD1 as an intramolecular adjuvant to develop a fusion DNA vaccine with HIV-1 Gag p24 antigen to immunize mice, which elicited a significantly enhanced level of anti-p24 IgG1/IgG2a antibody titers, and important p24-specific and tetramer(+)CD8(+) T cells responses that lasted for ≥7.5 months. Furthermore, p24-specific CD8(+) T cells remain functionally improved in proliferative and cytolytic capacities. Importantly, the enhanced antigen-specific immunity protected mice against pathogenic viral challenge and tumor growth. Thus, this newly identified PD1 variant (Δ42PD1) amplifies the generation of antigen-specific CD8(+) T cell immunity when used in a DNA vaccine.Molecular Therapy (2013); doi:10.1038/mt.2013.63.
    Molecular Therapy 04/2013; 21(7). DOI:10.1038/mt.2013.63 · 6.23 Impact Factor


9 Reads
Available from