IL-12 is required for anti-OX40-mediated CD4 T cell survival

CE Ruby, R Montler, R Zheng, S Shu… - The Journal of …, 2008 - journals.aai.org
CE Ruby, R Montler, R Zheng, S Shu, AD Weinberg
The Journal of Immunology, 2008journals.aai.org
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 …
Abstract
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.
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