HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ruby, C. E. Articles by Weinberg, A. D. PubMed PubMed Citation Articles by Ruby, C. E. Articles by Weinberg, A. D.

IL-12 Is Required for Anti-OX40-Mediated CD4 T Cell Survival

Carl E. Ruby^*, Ryan Montler^*, Rongxui Zheng, Suyu Shu and Andrew D. Weinberg^1,*

^* Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213; and Center for Surgery Research, Cleveland Clinic, Cleveland, OH 14495

Engagement of OX40 greatly improves CD4 T cell function and survival. Previously, we showed that both OX40 engagement and CTLA-4 blockade led to enhanced CD4 T cell expansion, but only OX40 signaling increased survival. To identify pathways associated with OX40-mediated survival, the gene expression of Ag-activated CD4 T cells isolated from mice treated with anti-OX40 and -CTLA-4 was compared. This comparison revealed a potential role for IL-12 through increased expression of the IL-12R-signaling subunit (IL-12Rβ2) on T cells activated 3 days previously with Ag and anti-OX40. The temporal expression of IL-12Rβ2 on OX40-stimulated CD4 T cells was tightly regulated and peaked 4–6 days after initial activation/expansion, but before the beginning of T cell contraction. IL-12 signaling, during this window of IL-12Rβ2 expression, was required for enhanced T cell survival and survival was associated with STAT4-specific signaling. The findings from these observations were exploited in several different mouse tumor models where we found that the combination of anti-OX40 and IL-12 showed synergistic therapeutic efficacy. These results may lead to the elucidation of the molecular pathways involved with CD4 T cell survival that contribute to improved memory, and understanding of these pathways could lead to greater efficacy of immune stimulatory Abs in tumor-bearing individuals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Andrew D. Weinberg at the current address: Laboratory of Basic Immunology, Robert W. Franz Cancer Research Center, 4805 NE Glisan Street, Portland, OR 97213. E-mail address: andrew.weinberg{at}providence.org

² Abbreviations used in this paper: LN, lymph node; TRAMP, transgenic adenocarcinoma of the mouse prostate; DC, dendritic cell.