Xiang, J, Huang, H and Liu, Y. A new dynamic model of CD8+ T effector cell responses via CD4+ T helper-antigen-presenting cells. J Immunol 174: 7497-7505

Research Unit, Saskatchewan Cancer Agency, Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
The Journal of Immunology (Impact Factor: 4.92). 07/2005; 174(12):7497-505. DOI: 10.4049/jimmunol.174.12.7497
Source: PubMed


A long-standing paradox in cellular immunology has been the conditional requirement for CD4(+) Th cells in priming of CD8(+) CTL responses. We propose a new dynamic model of CD4(+) Th cells in priming of Th-dependent CD8(+) CTL responses. We demonstrate that OT II CD4(+) T cells activated by OVA-pulsed dendritic cells (DC(OVA)) are Th1 phenotype. They acquire the immune synapse-composed MHC II/OVAII peptide complexes and costimulatory molecules (CD54 and CD80) as well as the bystander MHC class I/OVAI peptide complexes from the DC(OVA) by DC(OVA) stimulation and thus also the potential to act themselves as APCs. These CD4(+) Th-APCs stimulate naive OT I CD8(+) T cell proliferation through signal 1 (MHC I/OVAI/TCR) and signal 2 (e.g., CD54/LFA-1 and CD80/CD28) interactions and IL-2 help. In vivo, they stimulate CD8(+) T cell proliferation and differentiation into CTLs and induce effective OVA-specific antitumor immunity. Taken together, this study demonstrates that CD4(+) Th cells carrying acquired DC Ag-presenting machinery can, by themselves, efficiently stimulate CTL responses. These results have substantial implications for research in antitumor and other aspects of immunity.

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    • "Acquisition of MHC class I (MHC-I) peptide complexes by trogocytosis may provide antigenic targets for fratricide among CTL clones [30] or may simply reduce the concentration of antigen on the surface of APCs, thereby leading to a reduction in T cell stimulus [41]. It has been proposed that MHC-I molecules obtained by CD4 T cells via trogocytosis formed the basis for a novel and direct CD4∶CD8 T cell interaction that results in the provision of help for the CD8 T cells [42], but this model fails to account for signals that trigger effector functions of the CD4 T cells themselves because the CD8 T cells in this interaction do not present MHC-II/peptide complexes and therefore rely on the likelihood of encounters while TCR triggering is still maintained in CD4 T cells by endocytosed MHC-II molecules as suggested before [43]. "
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    ABSTRACT: Protection against many intracellular pathogens is provided by CD8 T cells, which are thought to need CD4 T cell help to develop into effective memory CD8 T cells. Because murine CD8 T cells do not transcribe MHC class II (MHC-II) genes, several models have proposed antigen presenting cells (APCs) as intermediaries required for CD4 T cells to deliver their help to CD8 T cells. Here, we demonstrate the presence of MHC-II molecules on activated murine CD8 T cells in vitro as well as in vivo. These MHC-II molecules are acquired via trogocytosis by CD8 T cells from their activating APCs, particularly CD11c positive dendritic cells (DCs). Transferred MHC-II molecules on activated murine CD8 T cells were functionally competent in stimulating specific indicator CD4 T cells. CD8 T cells that were "helped" in vitro and subsequently allowed to rest in vivo showed enhanced recall responses upon challenge compared to "helpless" CD8 T cells; in contrast, no differences were seen upon immediate challenge. These data indicate that direct CD8∶CD4 T cell interactions may significantly contribute to help for CD8 T cells. Furthermore, this mechanism may enable CD8 T cells to communicate with different subsets of interacting CD4 T cells that could modulate immune responses.
    PLoS ONE 02/2013; 8(2):e56999. DOI:10.1371/journal.pone.0056999 · 3.23 Impact Factor
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    • "In the absence of strong inflammatory signals, CD4+ T cells enhance CTL immunity either indirectly by licensing DCs [9]–[11], or directly by interacting with cognate CD8+ T cells [14], [38], [39]. Immunity to cancers, allogenic transplantations and autoimmune disorders thus requires CD4+ T cells for optimal priming, maintenance and memory responses [1], [8], [38], [40], [41]. "
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    ABSTRACT: Adenoviral (AdV) vectors represent most commonly utilized viral vaccines in clinical studies. While the role of CD8(+) cytotoxic T lymphocyte (CTL) responses in mediating AdV-induced protection is well understood, the involvement of CD4(+) T cell-provided signals in the development of functional CD8(+) CTL responses remain unclear. To explore CD4(+) T helper signals required for AdVova-stimulated CTL responses, we established an adoptive transfer system by transferring CD4(+) T cells derived from various knock out and transgenic mice into wild-type and/or CD4-deficient animals, followed by immunizing with recombinant ovalbumin (OVA)-expressing AdVova vector. Without CD4(+) T help, both primary and memory CTL responses were greatly reduced in this model, and were associated with increased PD-1 expression. The provision of OVA-specific CD4(+) T help in CD4(+) T cell-deficient mice restored AdVova-induced primary CTL responses, and supported survival and recall responses of AdVova-stimulated memory CTLs. These effects were specifically mediated by CD4(+) T cell-produced IL-2 and CD154 signals. Adoptive transfer of "helped" or "unhelped" effector and memory CTLs into naïve CD4(+) T cell-deficient or -sufficient mice also revealed an additional role for polyclonal CD4(+) T cell environment in the survival of AdVova-stimulated CTLs, partially explaining the extension of CTL contraction phase. Finally, during recall responses, CD4(+) T cell environment, particularly involving memory CD4(+) T cells, greatly enhanced expansion of memory CTLs. Collectively, our data strongly suggest a critical role for CD4(+) T help in multiple phases of AdV-stimulated CTL responses, and could partially explain certain failures in AdV-based immunization trials targeting malignant tumors and chronic diseases that are often associated with compromised CD4(+) T cell population and function.
    PLoS ONE 10/2012; 7(10):e47004. DOI:10.1371/journal.pone.0047004 · 3.23 Impact Factor
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    • "Human gp100 (hgp100) expression plasmid pWRG1644 was a kind gift from Dr Nicholas Restifo, National Cancer Institute, (Bethesda, MD USA). pWRG1644 plasmid without containing the coding sequence of hgp100 was used as a control [24]. The pORF9-mRANTES mammalian expression vector was purchased from Invivogen (San Diego, CA, USA). "
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    ABSTRACT: Shikonin, a phytochemical purified from Lithospermum erythrorhizon, has been shown to confer diverse pharmacological activities, including accelerating granuloma formation, wound healing, anti-inflammation and others, and is explored for immune-modifier activities for vaccination in this study. Transdermal gene-based vaccine is an attractive approach for delivery of DNA transgenes encoding specific tumor antigens to host skin tissues. Skin dendritic cells (DCs), a potent antigen-presenting cell type, is known to play a critical role in transmitting and orchestrating tumor antigen-specific immunities against cancers. The present study hence employs these various components for experimentation. The mRNA and protein expression of RANTES were detected by RT-PCR and ELISA, respectively. The regional expression of RANTES and tissue damage in test skin were evaluated via immunohistochemistry assay. Fluorescein isothiocyanate sensitization assay was performed to trace the trafficking of DCs from the skin vaccination site to draining lymph nodes. Adjuvantic effect of shikonin on gene gun-delivered human gp100 (hgp100) DNA cancer vaccine was studied in a human gp100-transfected B16 (B16/hgp100) tumor model. Among various phytochemicals tested, shikonin induced the highest level of expression of RANTES in normal skin tissues. In comparison, mouse RANTES cDNA gene transfection induced a higher level of mRANTES expression for a longer period, but caused more extensive skin damage. Topical application of shikonin onto the immunization site before gene gun-mediated vaccination augmented the population of skin DCs migrating into the draining lymph nodes. A hgp100 cDNA gene vaccination regimen with shikonin pretreatment as an adjuvant in a B16/hgp100 tumor model increased cytotoxic T lymphocyte activities in splenocytes and lymph node cells on target tumor cells. Together, our findings suggest that shikonin can effectively enhance anti-tumor potency of a gene-based cancer vaccine via the induction of RANTES expression at the skin immunization site.
    Journal of Biomedical Science 04/2012; 19(1):42. DOI:10.1186/1423-0127-19-42 · 2.76 Impact Factor
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