The IL-15/IL-15Rα on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells

Sato, Noriko; Patel, Himatkumar V.; Waldmann, Thomas A.; Tagaya, Yutaka

doi:10.1073/pnas.0610115104

Cited by 133 publications

(150 citation statements)

References 38 publications

Supporting

Mentioning

138

Contrasting

Order By: Relevance

“…Although we readily observe IL-15 trans-presentation using DCs pulsed in vitro with recombinant hIL-15, we could not ascertain this phenomenon in DCs isolated from the spleen following hydrodynamic gene transfer of hIL-15 in vivo (data not shown). Higher levels of circulating cytokine could be critical for this purpose as proposed by Sato et al 38 It remains to be seen if IKDCs also sense IL-15 via DC-mediated trans-presentation.…”

Section: Discussionmentioning

confidence: 95%

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

et al. 2008

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 95%

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Like in humans, CD27 high cells were found to be most abundant in lymphoid organs, while CD27 low cells, expressing increased levels of NK cell receptors, predominated in the circulation. In the lung, which contains particularly high levels of IL-15 due to effective recycling (44), NK cells were almost exclusively CD27 low . Notably, in contrast with the situation in humans, highest effector function was observed within the CD27 high subset.…”

Section: Discussionmentioning

confidence: 99%

CD27 Defines Phenotypically and Functionally Different Human NK Cell Subsets

Vossen

Matmati²,

Hertoghs³

et al. 2008

The Journal of Immunology

152

147

View full text Add to dashboard Cite

The absence of the TNF-receptor family member CD27 marks the stable acquisition of cytolytic effector functions by both CD4+ and CD8+ T cells. We found that the majority of circulating human NK cells was CD27−. These cells were largely CD56dim, contained high levels of perforin and granzyme B, and were able to exert strong cytotoxic activity. In contrast, circulating CD27+ NK cells were mostly CD56dim/bright, had significant lower levels of perforin and granzyme B, and had a low cytolytic potential. Primary and secondary lymphoid organs were markedly enriched for CD27+ NK cells. When correlating the expression of CD27 to recently defined developmental stages of NK cells in tonsil, we observed that CD27 was exclusively found on mature CD94+, stage 4 NK cells. On these cells, regulation of CD27 expression appeared to be controlled by the common γ-chain cytokine IL-15, and down-regulation of CD27 was specifically induced by its ligand, CD70. Thus, the absence of CD27 expression allows the definition of cytotoxic effector cells within the known mature NK cell subsets in humans.

show abstract

“…IL-2 is a soluble factor produced by activated T cells [21] whereas IL-15 is complexed with the IL-15 receptor a chain (IL-15Ra) and presented on the cell surface [22][23][24]. IL-15/IL-15Ra complexes undergo recycling without lysosomal degradation and therefore, membrane-bound IL-15 is well suited to provide continuous survival signals for receptive T cells [25][26][27]. Moreover, signaling by IL-15 but not IL-2 has been shown to upregulate the antiapoptotic protein Bcl-x L in anti-CD3-stimulated human T cells [18].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

2008

View full text Add to dashboard Cite

We determined the efficacy of in vitro expanded P14 TCR transgenic CD8 T cells to mediate tumor cell elimination and to protect against viral infection in mice. Contrary to previous studies, an adoptive transfer model without lymphodepletion, vaccination or cytokine treatment was used. Antigen-activated P14 T cells cultured in IL-2-containing medium for 7 days (P14 IL-2 ) exhibited potent effector cell functions in vitro but did not confer protection against melanoma growth or viral infection. In contrast, P14 T cells cultured in IL-15 (P14 ) were highly effective in vivo although they displayed only moderate effector functions in vitro. Therapeutic efficacy correlated with the survival of the transferred T cells in the recipients: P14 IL-2 cells disappeared rapidly whereas P14 IL-15 cells persisted for prolonged time. Decreasing the IL-2 concentration in the culture media improved in vivo survival and efficacy but also lowered the cell yield of the cultures. Finally, we could extend the findings with monoclonal P14 T cells to polyclonal CD8 T cells. Thus, in vitro expansion of antigen-specific CD8 T cells in IL-15 allowed the generation of substantial numbers of T cells without inducing terminally differentiated effector cells that turned out to be unfavorable in the transfer model examined here.Key words: Cytotoxic T cells . Rodent . Tumor immunity . Viral IntroductionAdoptive transfer of antigen-specific CD8 T cells into hosts represents a promising approach to treat tumors and viral infections [1][2][3][4]. To generate sufficient numbers of T cells for this therapy, T cells have to be stimulated and expanded in vitro. In most protocols used today, IL-2 is added to the culture medium to ensure T-cell proliferation, differentiation and survival. Besides IL-2, IL-15 also supports CD8 T-cell growth [5]; however, the phenotype and the functional activity of IL-2-versus IL-15-cultured CD8 T cells differ considerably. Manjunath et al. [6] were the first to show that CD8 T cells from P14 TCR-tg mice specific for gp33 epitope of lymphocytic choriomeningitis virus (LCMV) acquired an effector memory phenotype with high cytolytic activity when cultured in the presence of IL-2 whereas addition of IL-15 led to a central memory phenotype with low effector cell functions. Further analysis in the same TCR transgenic system revealed that these two cytokines were equivalent mitogens for antigen-stimulated CD8 T cells but that IL-2 was more potent in inducing amino acid uptake and protein synthesis [7].For adoptive T-cell therapy, it is important to generate CD8 T cells in vitro, which are efficient in inducing tumor regression or virus clearance in vivo. The degree of specific target cell lysis and the amount of antigen-triggered IFN-g production are frequently used to predict the efficacy of CD8 T cells in vivo. However, several recent studies in the pmel-1 TCR-tg model specific for the self/tumor antigen gp100 of B16 melanoma cells indicated that antigen-stimulated CD8 T cells with a less differentiated phenotype were sup...

show abstract

The IL-15/IL-15Rα on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells

Abstract: cytokine retention in vivo ͉ memory CD8 homing

Cited by 133 publications

References 38 publications

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

CD27 Defines Phenotypically and Functionally Different Human NK Cell Subsets

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Contact Info

Product

Resources

About