The Roles of IL-12 in Providing a Third Signal for Clonal Expansion of Naive CD8 T Cells

Abstract

Stimulation of an effective in vitro or in vivo response by naive CD8 T cells requires three signals: TCR engagement, costimulation/IL-2, and a third signal that can be provided by IL-12. In addition to being required for acquisition of cytolytic function, IL-12 is required for optimal IL-2-dependent proliferation and clonal expansion. In experiments examining in vitro stimulation of naive CD8 T cells, IL-12 is shown to stimulate expression of the IL-2R α-chain (CD25) to much higher levels than are reached in response to just TCR and costimulation and/or IL-2. In addition, high CD25 expression is substantially prolonged in the presence of IL-12. As a consequence, the cells proliferate more effectively in response to low levels of IL-2. Examination of adoptively transferred TCR transgenic CD8 T cells responding to peptide Ag confirmed that IL-12 up-regulates CD25 in vivo, even when B7-mediated costimulation is largely blocked. TCR- and IL-2-dependent proliferation of CD8 T cells from mice deficient in CD25 was also found to increase in the presence of IL-12, indicating that CD25 up-regulation is not the only mechanism by which IL-12 increases clonal expansion of the cells. IL-2 and IL-12 both act to increase expression of both CD25 and the IL-12R, thus providing positive cross-regulation of receptor expression. These results suggest that when cross-priming dendritic cells present class I/Ag and costimulatory ligands, and produce IL-12, naive CD8 T cells will begin to produce IL-2 and both receptors will be optimally up-regulated to insure that an effective response is generated.

Priming of naive CD8+ T cells in the presence of IL-12 selectively enhances the survival of CD8+CD62Lhi cells and results in superior anti-tumor activity in a tolerogenic murine model

“…In support of these findings, Chang et al reported that IL-12 priming at the time of antigenic stimulation increased the primary expansion of CD8 + T cells by reducing cell death, rather that by increasing cell proliferation, resulting in a larger CD8 + T cell memory pool [4]. The ability of IL-12 to enhance proliferation of activated CD8 + T cells has been recently associated with enhanced expression of IL-2Rα in response to IL-12R engagement [35]. IL-12R expression is upregulated upon TCR activation [9], however low levels of expression have been reported in resting NK cells, dendritic cells and B cell lines [1,12].…”

“…IL-12 can also directly affect the development of CD8 + T cell-mediated responses. It is known that optimal clonal expansion and acquisition of effector function requires a third signal that can be provided by IL-12, and that in the absence of third signal, tolerance can occur [6,7,29,30,35,36]. In support of these findings, Chang et al reported that IL-12 priming at the time of antigenic stimulation increased the primary expansion of CD8 + T cells by reducing cell death, rather that by increasing cell proliferation, resulting in a larger CD8 + T cell memory pool [4].…”

“…Of significant interest has also been the role of inflammatory cytokines such as IL-12. In addition to its role in polarizing Th1 responses and in the maturation of cytotoxic functions of CTLs and NK cells [38], IL-12 acts as a third signal along with antigen and IL-2 on naive CD8 + T cells increasing the pool of effector and memory cells [6,35,36]: two crucial components of a successful ACT approach. Evidence for this has been provided in recent reports demonstrating increased anti-tumor capabilities of CD8 + T cells after ex vivo culture in the presence of IL-12 [8,18].…”

Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

“…2E). It is worth noting that IL-12 is known also to serve as a ''third signal'' for activated T cells [38,41,42]. In conclusion, we suggest a model in which MVA infection induces IFN that concomitantly acts directly on T cells and on DC to promote T-cell expansion, whereas VACV infection induces IL-12 that may compensate for leaking IFN and thus promotes IFNAR-independent T-cell expansion.…”

Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming

“…These effects of tumour cell fusion on DC phenotype and cytokine production may influence their interaction with naive T cells, 10 potentially facilitating priming by DC of an antitumour cytotoxic T-cell response. Therefore, the ability of fusing vs nonfusing tumour cell-loaded DC to prime a human naive T-cell response against Mel888 was determined.…”