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The Journal of Immunology, 2001, 167: 5678-5688.
Copyright © 2001 by The American Association of Immunologists

CD40 Ligand Promotes Priming of Fully Potent Antitumor CD4+ T Cells in Draining Lymph Nodes in the Presence of Apoptotic Tumor Cells

Nanae Fujita*, Hiroshi Kagamu*, Hirohisa Yoshizawa1,*, Kazuhisa Itoh*, Hideyuki Kuriyama*, Naoya Matsumoto*, Takuro Ishiguro*, Junta Tanaka*, Eiichi Suzuki*, Hirofumi Hamada{dagger} and Fumitake Gejyo*

* Department of Medicine (II), Niigata University Medical School, Niigata, Japan; and {dagger} Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

The presence or absence of CD4+ T cell help can determine the direction of adaptive immune responses toward either cross-priming or cross-tolerance. It has been demonstrated that interactions of CD40-CD40 ligand can replace CD4+ T cell help and enable dendritic cells to prime cytotoxic T cells. Here, we demonstrate that antitumor reactivity induced in regional lymph nodes (LNs) by s.c. injection of CD40 ligand (CD40L)-transduced tumor (MCA205 CD40L) showed far superior therapeutic efficacy against established brain tumors of a weakly immunogenic fibrosarcoma, MCA205, when adoptively transferred. Coinjection of apoptotic, but not necrotic parental tumor cells with CD40L-expressing tumor cells caused a strong synergistic induction of antitumor reactivity in tumor-draining LNs. Freshly isolated T cells from LNs immunized with apoptotic parental tumor cells and MCA205 CD40L were capable of mediating regression of the parental tumor in vivo. In contrast, T cells derived from LNs immunized without MCA205 CD40L required ex vivo anti-CD3/IL-2 activation to elicit therapeutic activity. On anti-CD3/IL-2 activation, cells from LNs immunized with MCA205 CD40L exhibited superior per cell antitumor reactivity. An in vitro depletion study revealed that either CD4+ or CD8+ T cells could mediate therapeutic efficacy but that the antitumor efficacy mediated by CD4+ T cells was far superior. Cytosolic flow cytometric analyses indicated that priming of CD4+ cells in LNs draining CD40L-expressing tumors was polarized to the Th1 type. This is the first report that fully potent antitumor CD4+ T cell priming was promoted by s.c. injection of CD40L-transduced tumor in the presence of apoptotic tumor cells.




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