Ex Vivo Expansion of Human CD8+ T Cells Using Autologous CD4+ T Cell Help
Butler, Marcus O.
Milstein, Matthew I.
Mooney, Mary M.
Murray, Andrew P.
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CitationButler, Marcus O., Osamu Imataki, Yoshihiro Yamashita, Makito Tanaka, Sascha Ansén, Alla Berezovskaya, Genita Metzler, Matthew I. Milstein, Mary M. Mooney, Andrew P. Murray, Hiroyuki Mano, Lee M. Nadler, and Naoto Hirano. 2012. Ex vivo expansion of human cd8+ t cells using autologous cd4+ t cell help. PLoS ONE 7(1): e30229.
AbstractBackground: 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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