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

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.

Depleting tumor-specific Tregs at a single site eradicates disseminated tumors

“…This question is of the utmost importance both for fundamental immunology and for clinical practice. Indeed, the original experiments of Medawar showed that the brain is an immunologically privileged site for skin allografts (45, Indeed, others have shown that OX40, CTLA-4, and CpG could all alter the suppressive properties and, in some cases, the phenotype of Tregs (8,27,(36)(37)(38)(39)(40)(41)(42)(43)(44). However, we ruled out this hypothesis by tracking the Tregs in vivo: the addition of CpG to immunomodulatory antibody therapy resulted in the depletion of i.t.…”

Stimulation of the histamine 4 receptor with 4-methylhistamine modulates the effects of chronic stress on the Th1/Th2 cytokine balance

“…Further, Ox40 signaling is known to augment secretion of IL-2 and IFN-␥ by activated CD4T cells (Ruby et al 2008). These studies have implied that a major role of Ox40 is to regulate the number of T cells that accumulate during primary immune responses, and consequently to promote production of a large number of memory T cells.…”

Is it wise to target the late costimulatory molecule OX40 as a therapeutic target?

“…Both molecules are membrane bound and trimerization is required for signaling, another common feature of TNF/TNFR superfamily members [10]. Following ligation, OX40-expressing T cells receive signals that result in the transcription of anti-apoptotic factors, such as certain members of the Bcl-2 family [47], and the increase in expression of cytokine receptors such as the IL-12 receptor [48] (see Fig. 1).…”

“…TRAF molecules initiate phosphorylation cascades which result in the activation and translocation to the nucleus of transcription factors such as NFκB and c-Jun N-terminal kinase. Ruby et al [48] describe a number of genes that are affected by OX40 signaling, including the β chain of the IL-12 receptor, which signals through the transcription factor Stat4 and is required for OX40-mediated T cell survival. Furthermore, the reported up-regulation of the IL-2 receptor's α chain [45] would augment IL-2 signaling.…”