IntroductionInterleukin-17 (IL-17), originally identified by Rouvier et al 1 as cytolytic T-lymphocyte (CTL)-associated antigen 8, is a T-cellderived cytokine with homology to Herpesvirus saimiri. [1][2] It is expressed mainly by activated CD4 ϩ CD45RO ϩ memory T cells. [3][4] CD4 T cells can be classified into T-helper (Th) 1 cells, which secrete interferon (IFN) ␥, IL-2, and tumor necrosis factor (TNF) ; Th2 cells, which produce IL-4, IL-5, IL-6, IL-10, and IL-13; and Th0 cells, a common precursor with the ability to release both IFN␥ and IL-4. Thirty percent of Th0/Th1 clones have been shown to produce IL-17, whereas Th2 clones never express IL-17. 5 IL-2 and IL-15 were found to increase IL-17 production by human peripheral blood (PB) mononuclear cells. 6 IL-17 is considered to be a proinflammatory cytokine because it increases IL-6 and IL-8 production by macrophages, fibroblasts, keratinocytes, and synovial cells 2,3,[7][8][9] and nitric oxide production by human osteoarthritic cartilage. 10,11 IL-17 also induces secretion of IL-1 and TNF-␣ by human macrophages and endothelial cells. 7,12 IL-17 activates the nuclear factor B and activator protein 1 transcription factors, which may explain its proinflammatory properties. 10,13 In addition, IL-17 induces production of granulocyte colony-stimulating factor and CXC chemokines that stimulate granulopoiesis and recruitment of neutrophils into tissues. [14][15][16] The IL-17 receptor is a type I transmembrane protein that is expressed in virtually all cells and tissues, in contrast to the restricted expression of IL-17, which is confined to T cells. 2,17 This receptor has no sequence similarity with any other known cytokine receptor. It interacts with the adapter molecule TNF receptorassociated factor 6, which is required for IL-17 signaling. 18 The exact role of IL-17 in disease is unknown. IL-17 has been found to promote cartilage destruction in various forms of arthritis. 19,20 Overproduction of IL-17 has been observed in the synovium of patients with rheumatoid arthritis 21 and in PB lymphocytes from patients with systemic sclerosis. 22 In a previous study, we found that IL-17 promotes tumorigenicity of human cervical tumors in nude mice. 23 Because this paradoxical tumor-promoting activity of IL-17 in the absence of T cells was unexpected, we conducted the current study to analyze the effect of IL-17 on the growth of syngeneic tumors in immunocompetent mice. We found that IL-17 inhibits the growth of 2 hematopoietic tumors, mastocytoma P815 and plasmocytoma Materials and methods Mice and tumor cell linesFemale Balb/c, DBA/2, and athymic nude/nude mice 6 to 8 weeks of age (Iffa Credo L'Arbresle, France) were used in this study. The mouse plasmocytoma J558L and mastocytoma P815 cell lines were obtained from the American Type Culture Collection (Manassas, VA). The mouse squamous cell carcinoma KLN 205 was purchased from the European Collection of Cell Culture (Salisbury, Wiltshire, United Kingdom). The cell lines were cultured in RPMI supplemented with 10% fet...
Adoptive transfer of Ag-specific T lymphocytes is an attractive form of immunotherapy for cancers. However, acquiring sufficient numbers of host-derived tumor-specific T lymphocytes by selection and expansion is challenging, as these cells may be rare or anergic. Using engineered T cells can overcome this difficulty. Such engineered cells can be generated using a chimeric Ag receptor based on common formats composed from Ag-recognition elements such as αβ-TCR genes with the desired specificity, or Ab variable domain fragments fused with T cell–signaling moieties. Combining these recognition elements are Abs that recognize peptide-MHC. Such TCR-like Abs mimic the fine specificity of TCRs and exhibit both the binding properties and kinetics of high-affinity Abs. In this study, we compared the functional properties of engineered T cells expressing a native low affinity αβ-TCR chains or high affinity TCR-like Ab–based CAR targeting the same specificity. We isolated high-affinity TCR-like Abs recognizing HLA-A2-WT1Db126 complexes and constructed CAR that was transduced into T cells. Comparative analysis revealed major differences in function and specificity of such CAR-T cells or native TCR toward the same antigenic complex. Whereas the native low-affinity αβ-TCR maintained potent cytotoxic activity and specificity, the high-affinity TCR-like Ab CAR exhibited reduced activity and loss of specificity. These results suggest an upper affinity threshold for TCR-based recognition to mediate effective functional outcomes of engineered T cells. The rational design of TCRs and TCR-based constructs may need to be optimized up to a given affinity threshold to achieve optimal T cell function.
A number of studies in animal models and humans have shown that both humoral andcell-mediated immune responses play an important role in the control of viral infection and tumor development. In most cases, vaccination with non-vectorized peptides or proteins induces low antibody responses and fails to elicit specific cytotoxic T lymphocytes (CTL). In order to make vaccination more efficient, we chemically coupled the non-toxic B subunit of Shiga toxin (STxB) to a full-size antigenic model protein, ovalbumin (OVA), yielding STxB-OVA. We found that STxB-OVA delivers OVA-derived peptides into both the MHC class I- and II-restricted presentation pathways in mouse dendritic cells. Accordingly, the study of STxB trafficking in these cells revealed that, after internalization, a fraction of STxB followed the retrograde transport pathway to the endoplasmic reticulum, while another fraction was targeted to late endosomes/lysosomes. Vaccination of mice with STxB-OVA primed a specific anti-OVA CTL response without the use of adjuvants. Splenocytes and, particularly, CD4(+) T cells from mice immunized with STxB-OVA also produced higher amounts of the T(h)1 cytokine IFN-gamma and IgG2a-type antibodies than mice immunized with non-vectorized ovalbumin. In conclusion, this study identifies a unique non-live vaccine delivery system for polyepitopic antigens that elicits antigen-specific CTL, a humoral immune response and a T(h)1-type polarization without the use of adjuvant.
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