Defect of CD8+ Memory T Cells Developed in Absence of IL-12 Priming for Secondary Expansion

Ye, Zhenmin; Xu, Shulin; Moyana, Terence; Yang, Jicheng; Xiang, Jim

doi:10.1038/cmi.2008.18

Cited by 12 publications

(12 citation statements)

References 13 publications

(17 reference statements)

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“…Our study taken together with current literature, collectively support a model in which IL-12 and IL-23 serve as rheostats, translating the severity of an infection and influencing the resultant level of response (2, 7, 8, 11, 32, 34, 36, 56, 59, 60, 63). If IL-12/23 is abundant, memory generation is delayed in favor of the generation of SLECs with the intent of resolving the infection.…”

Section: Discussionsupporting

confidence: 78%

“…More recent studies however, have demonstrated that IL-12 does not alter the generation of memory precursor effector cells (MPEC) (7, 37). In addition, several reports have observed that IL-12 enhances the generation and function (increased secondary expansion upon antigen reencounter) of memory CD8+ T cells (12, 59, 60). Together, these studies highlight the importance of IL-12 in memory cell generation, but the nature of the effect may be modulated based on the relative intensity of the overall inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The roles of IL-12 and IL-23 in CD8+ T cell-mediated immunity against Listeria monocytogenes: Insights from a DC vaccination model

Henry

Grayson

Brzoza-Lewis

et al. 2010

Cellular Immunology

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Listeria monocytogenes infection induces a strong inflammatory response characterized by the production of IL-12 and IFN-γ and protective immunity against this pathogen is dependent on CD8 + T cells (CTL). Recent studies have suggested that these inflammatory cytokines affect the rate of memory CD8+ T cell generation as well as the number of short lived effector cells generated. The role of the closely related cytokine, IL-23, in this response has not been examined. We hypothesized that IL-12 and IL-23 produced by dendritic cells collectively enhance the generation and function of memory cells. To test this hypothesis, we employed a DC vaccination approach. Mice lacking IL-12 and IL-23 were vaccinated with wild-type (WT), IL-12−/−, or IL-12/23−/− DC and protection to Lm was monitored. Mice vaccinated with WT and IL-12−/− DC were resistant to lethal challenge with Lm. Surprisingly, mice vaccinated with IL-12/23−/− DC exhibited significantly reduced protection when challenged. Protection correlated with the relative size of the memory pools generated. In summary, these data indicate that IL-23 can partially compensate for the lack of IL-12 in the generation protective immunity against Lm.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

The roles of IL-12 and IL-23 in CD8+ T cell-mediated immunity against Listeria monocytogenes: Insights from a DC vaccination model

Henry

Grayson

Brzoza-Lewis

et al. 2010

Cellular Immunology

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“…IL-12 and IL-21 play pivotal roles in memory formation and the facilitation of antigen presentation [22, 25], and IL-7 sustains homeostatic T-cell expansion after initial ttRNA–DC priming. IL-15 was not selected as its functionality is similar to IL-2, and it has shown no effect in preserving CD62L expression [30].…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, IL-7 directly inhibits T Regs function and releases the natural regulatory brakes on T cells via signaling through the high-affinity IL-7R present on both naïve and memory T Regs [19]. Except cytokines sharing γc chain receptors, IL-12 is another important cytokine, which plays a pivotal role in the regulation of T-cell differentiation and memory formation [20-22], and the priming of naïve CD8 + T cells with IL-12 selectively enhances the survival of CD8 + CD62L high cells and results in superior anti-tumor activity in a tolerogenic murine model [23]. Compared to IL-2, it has been demonstrated that IL-7 and IL-21 could preserve less-differentiated effector T cells and enrich for tumor-reactive CD8 + T cells [24-26].…”

Section: Introductionmentioning

confidence: 99%

A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model

Yang

Archer

Flores

et al. 2013

Cancer Immunol Immunother

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Adoptive cell transfer (ACT) using ex vivo-expanded anti-tumor T cells such as tumor-infiltrated lymphocytes or genetically engineered T cells potently eradicates established tumors. However, these two approaches possess obvious limitations. Therefore, we established a novel methodology using total tumor RNA (ttRNA) to prime dendritic cells (DC) as a platform for the ex vivo generation of anti-tumor T cells. We evaluated the antigen-specific expansion and recognition of T cells generated by the ttRNA–DC–T platform, and directly modulated the differentiation status of these ex vivo-expanded T cells with a cytokine cocktail. Furthermore, we evaluated the persistence and in vivo anti-tumor efficacy of these T cells through murine xenograft and syngeneic tumor models. During ex vivo culture, IL-2 preferentially expanded CD4 subset, while IL-7 enabled homeostatic proliferation from the original precursors. T cells tended to lose CD62L during ex vivo culture using IL-2; however, IL-12 could maintain high levels of CD62L by increasing expression on effector T cells (Tem). In addition, we validated that OVA RNA–DC only selectively expanded T cells in an antigen-specific manner. A cytokine cocktail excluding the use of IL-2 greatly increased CD62Lhigh T cells which specifically recognized tumor cells, engrafted better in a xenograft model and exhibited superior anti-tumor activities in a syngeneic intracranial model. ACT using the ex vivo ttRNA–DC–T platform in conjunction with a cytokine cocktail generated potent CD62Lhigh anti-tumor T cells and imposes a novel T cell-based therapeutic with the potential to treat brain tumors and other cancers.

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“…For instance, IL-12 has been tested for its ability to promote T-cell differentiation and memory formation [46,47]. Interestingly, combinations of IL-7 plus IL-12 or IL-21 plus IL-12, followed by withdrawal of IL-12, were found to upregulate genes associated with stemness (e.g., SOX2, NANOG, OCT4), and to even revert the differentiation state of TILs derived from melanoma patients [48].…”

Section: On the Use Of Cytokines For Tumorreactive T Lymphocyte Expanmentioning

confidence: 97%

Exploiting Cytokines in Adoptive T-Cell Therapy of Cancer

Petrozziello¹,

Sturmheit

Mondino³

2015

Immunotherapy

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Adoptive immunotherapy with tumor-reactive autologous T cells, either expanded from tumor specimens or genetically engineered to express tumor-reactive T-cell receptors and chimeric antigen receptors, is holding promising results in clinical trials. Several critical issues have been identified and results underline the possibility to exploit cytokines to further ameliorate the efficacy of current treatment protocols, also encompassing adoptive T-cell therapy. Here we review latest developments on the use of cytokines to better direct the nature of the T-cell infusion product, T-cell function and persistence in vivo, as well as to modulate the tumor microenvironment.

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Defect of CD8+ Memory T Cells Developed in Absence of IL-12 Priming for Secondary Expansion

Cited by 12 publications

References 13 publications

The roles of IL-12 and IL-23 in CD8+ T cell-mediated immunity against Listeria monocytogenes: Insights from a DC vaccination model

The roles of IL-12 and IL-23 in CD8+ T cell-mediated immunity against Listeria monocytogenes: Insights from a DC vaccination model

A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model

Exploiting Cytokines in Adoptive T-Cell Therapy of Cancer

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