CD28 costimulation is required not only to induce IL-12 receptor but also to render Janus kinases / STAT4 responsive to IL-12 stimulation in TCR-triggered T cells

Park, Woong Ryeon; Park, Cheung Seog; Tomura, Michio; Ahn, Hyung Joon; Nakahira, Yasukiyo; Iwasaki, Masayuki; Gao, Ping; Ryo, Akihide; Hamaoka, Toshiyuki; Fujiwara, Hiromi

doi:10.1002/1521-4141(200105)31:5<1456::aid-immu1456>3.0.co;2-a

Cited by 17 publications

(11 citation statements)

References 36 publications

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“…37 Although IL-12 is necessary for full activation of CD8 T cells, exogenously added IL-12 did not modify tolerance induction by LSEC (data not shown and Limmer et al 21 ). Because expression of the IL-12 receptor is dependent on CD28 costimulation, 38 the low surface expression of CD80/CD86 on LSEC may ensure that CD8 T cells stimulated by LSEC do not become receptive for IL-12. Thus, the functional phenotype of LSEC favors co-inhibition over costimulation and determines their tolerogenic function.…”

Section: Discussionmentioning

confidence: 99%

Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance

et al. 2008

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Section: Discussionmentioning

confidence: 99%

Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance

et al. 2008

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“…In addition to each cytokine increasing the expression of its own receptor, cross-regulation of CD25 and IL-12R␤1/␤2 expression by IL-2 and IL-12 has been demonstrated in CD4 T cells; IL-2 and/or B7 costimulation can increase the expression of IL-12R (22)(23)(24)(25), and IL-12 can up-regulate CD25 over levels achieved by IL-2 or B7-1 (26 -29). As mentioned above, the significance of CD25 regulation by IL-12 in CD4 cells is unclear, because IL-12 does not increase in vivo clonal expansion of these cells in response to Ag (44).…”

Section: Discussionmentioning

confidence: 99%

“…Mature resting T cells do not express CD25, but it can be rapidly and transiently up-regulated by TCR and CD28 ligation and by several cytokines including IL-2 (15). Cross-regulation of CD25 and IL-12R␤1/␤2 expression by IL-2 and IL-12 has been studied in CD4 T cells, with the results indicating that IL-2 and/or B7 costimulation can increase the expression of IL-12R (22)(23)(24)(25), and that IL-12 can up-regulate CD25 over levels achieved by IL-2 or B7-1 (26 -29).…”

mentioning

confidence: 99%

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

Valenzuela

Schmidt

Mescher

2002

The Journal of Immunology

178

184

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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.

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“…Furthermore, it has been demonstrated in mice that CD28 costimulation, acting through IL-2, is necessary for both the normal expression of IL-12R␤2 and subsequent differentiation of autoreactive effector cells (26). This requirement for CD28 signaling may impact not only the level of IL-12R surface expression, but also the receptors ability to signal as well (47).…”

Section: Discussionmentioning

confidence: 99%

IL-2 Receptor Blockade Inhibits Late, But Not Early, IFN-γ and CD40 Ligand Expression in Human T Cells: Disruption of Both IL-12-Dependent and -Independent Pathways of IFN-γ Production

McDyer

John

et al. 2002

The Journal of Immunology

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mAbs directed against the α-chain (Tac/CD25) of the IL-2R are an emerging therapy in both transplantation and autoimmune disease. However, the mechanisms underlying their therapeutic efficacy have not been fully elucidated. Therefore, we examined the affect of IL-2R blockade on Th1 and Th2 cytokine production from human PBMC. Addition of a humanized anti-Tac Ab (HAT) to activated PBMC cultures inhibited IFN-γ production from CD4 and CD8 T cells by 80–90%. HAT partially inhibited production of TNF-α and completely inhibited production of IL-4, IL-5, and IL-10. Furthermore, IL-12, a central regulatory cytokine that induces IFN-γ, was undetectable in treated cultures. As T cell-dependent induction of IL-12 is regulated via CD40/CD40 ligand (CD40L) interactions, we examined the affect of HAT on CD40L expression. We found CD40L expression to be biphasic with an early (6 h) peak that is CD28/IL-2-independent, but a later peak (48 h) being CD28/IL-2-dependent and inhibited by HAT. Similarly, IFN-γ production at 6 h was CD28/IL-2-independent but CD28/IL-2-dependent and inhibited by HAT at 48 h. Nonetheless, addition of rCD40L or exogenous IL-12 to HAT-treated cultures could not restore IFN-γ production. The IFN-γ deficit in such cultures appears to be due to a direct inhibition by HAT of IL-12-independent IFN-γ production from T cells rather than altered expression of either the IL-12Rβ1 or IL-12Rβ2 chains. These data demonstrate that IL-2 plays a critical role in the regulation of Th1 and Th2 responses and impacts both IL-12-dependent and -independent IFN-γ production.

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CD28 costimulation is required not only to induce IL-12 receptor but also to render Janus kinases / STAT4 responsive to IL-12 stimulation in TCR-triggered T cells

Cited by 17 publications

References 36 publications

Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance

Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance

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

IL-2 Receptor Blockade Inhibits Late, But Not Early, IFN-γ and CD40 Ligand Expression in Human T Cells: Disruption of Both IL-12-Dependent and -Independent Pathways of IFN-γ Production

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