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.
    Full-text · Article · Feb 2013 · PLoS ONE
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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.
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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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    Full-text · Article · Apr 2012 · Journal of Biomedical Science
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