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International Immunology Advance Access published online on July 18, 2005
International Immunology, doi:10.1093/intimm/dxh288
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Received November 15, 2004
Accepted May 27, 2005

Article

B7.2-Ig fusion proteins enhance IL-4-dependent differentiation of tumor-sensitized CD8+ cytotoxic T lymphocyte precursors

Shin-ichiro Hiraoka 1, Noritami Takeuchi 1, Yang Bian 1, Hirokazu Nakahara 2, Mikihiko Kogo 2, Kyriaki Dunussi-Joannopoulos 3, Stanley Wolf 3, Shiro Ono 1*, and Hiromi Fujiwara 1

1 Department of Oncology (C6), Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan
2 First Department of Oral and Maxillo-facial surgery, Faculty of Dentistry, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan
3 Department of Inflammation, Wyeth Research, Cambridge, MA 02140, USA

* To whom correspondence should be addressed.
Shiro Ono, E-mail: sono{at}ongene.med.osaka-u.ac.jp


  Abstract

The B7/CD28 co-stimulatory pathway plays a critical role in T cell activation and differentiation. Our previous study demonstrated that administration of B7.2-Ig fusion proteins to tumor-bearing mice elicits IL-4-dependent, CD8+ T cell-mediated tumor regression. Here, we investigated whether B7.2-Ig stimulation of tumor-sensitized CD8+ CTL precursors during in vitro antigen re-sensitization actually results in their differentiation into mature CTLs and if so, whether such a process depends on IL-4 signals. Splenocytes from tumor-sensitized (tumor-bearing or tumor-immunized) mice exhibited low levels of anti-tumor CTL responses upon culturing alone, but induced strikingly enhanced CTL responses when stimulated in vitro with B7.2-Ig fusion proteins. Because CTLs were not generated from normal splenocytes even by B7.2-Ig stimulation, the expression of the B7.2-Ig effect required the in vivo tumor sensitization of CD8+ CTL precursors. Administration of anti-CD4 or anti-CD40 ligand (CD40L) to mice before tumor sensitization resulted in almost complete inhibition of CTL responses generated in the subsequent culture containing B7.2-Ig. In contrast, anti-IL-4 did not influence in vivo tumor sensitization required for CTL induction. However, B7.2-Ig stimulation of tumor-sensitized splenocytes enhanced IL-4 production and neutralization of this IL-4 with anti-IL-4 potently down-regulated CTL responses. These results indicate that B7.2-Ig enhances IL-4-dependent differentiation of anti-tumor CD8+ CTL precursors that can be sensitized in vivo depending on collaboration with CD4+ T cells involving CD40L function.

Keywords: costimulation; Th1/Tc2; Th2/Tc2; tumor immunity; CD40L.
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