Abstract
BackgroundUsing 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 FindingsWe 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.ConclusionsWe 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.
Highlights
It is well accepted that neoplastic cells are immunogenic and that tumors develop in the context of immune recognition by the host [1,2]
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
Summary
It is well accepted that neoplastic cells are immunogenic and that tumors develop in the context of immune recognition by the host [1,2]. Anti-tumor T cell responses, with infiltration of tumors by CD8+ T lymphocytes and local production of interferon-c and IL-2, have been associated with improved clinical prognosis [5,6,7,8]. Tumor infiltration by T regulatory (Treg) cells has been correlated with inferior clinical outcomes in several tumors [10,11]. These findings have led to the proposal that immune recognition of cancer involves the balancing of opposing forces: anti-tumor effectors vs pro-tumor regulatory elements [10,12,13]. Our goal was to elucidate the mechanisms of human CD4+ T cell help of CD8+ T cell proliferation using a novel in vitro model
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