[HTML][HTML] Ex Vivo Expansion of Human CD8+ T Cells Using Autologous CD4+ T Cell Help

MO Butler, O Imataki, Y Yamashita, M Tanaka… - PloS one, 2012 - journals.plos.org
MO Butler, O Imataki, Y Yamashita, M Tanaka, S Ansén, A Berezovskaya, G Metzler…
PloS one, 2012journals.plos.org
Background Using in vivo mouse models, the mechanisms of CD4+ T cell help have been
intensively investigated. However, a mechanistic analysis of human CD4+ T cell help is
largely lacking. Our goal was to elucidate the mechanisms of human CD4+ T cell help of
CD8+ T cell proliferation using a novel in vitro model. Methods/Principal Findings We
developed a genetically engineered novel human cell-based artificial APC, aAPC/mOKT3,
which expresses a membranous form of the anti-CD3 monoclonal antibody OKT3 as well as …
Background
Using in vivo mouse models, the mechanisms of CD4+ T cell help have been intensively investigated. However, a mechanistic analysis of human CD4+ T cell help is largely lacking. Our goal was to elucidate the mechanisms of human CD4+ T cell help of CD8+ T cell proliferation using a novel in vitro model.
Methods/Principal Findings
We developed a genetically engineered novel human cell-based artificial APC, aAPC/mOKT3, which expresses a membranous form of the anti-CD3 monoclonal antibody OKT3 as well as other immune accessory molecules. Without requiring the addition of allogeneic feeder cells, aAPC/mOKT3 enabled the expansion of both peripheral and tumor-infiltrating T cells, regardless of HLA-restriction. Stimulation with aAPC/mOKT3 did not expand Foxp3+ regulatory T cells, and expanded tumor infiltrating lymphocytes predominantly secreted Th1-type cytokines, interferon-γ and IL-2. In this aAPC-based system, the presence of autologous CD4+ T cells was associated with significantly improved CD8+ T cell expansion in vitro. The CD4+ T cell derived cytokines IL-2 and IL-21 were necessary but not sufficient for this effect. However, CD4+ T cell help of CD8+ T cell proliferation was partially recapitulated by both adding IL-2/IL-21 and by upregulation of IL-21 receptor on CD8+ T cells.
Conclusions
We have developed an in vitro model that advances our understanding of the immunobiology of human CD4+ T cell help of CD8+ T cells. Our data suggests that human CD4+ T cell help can be leveraged to expand CD8+ T cells in vitro.
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