Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function

Zeng, Rong; Spolski, Rosanne; Finkelstein, Steven E.; Oh, Sang Kon; Kovanen, Panu E.; Hinrichs, Christian S.; Pise-Masison, Cynthia A.; Radonovich, Michael F.; Brady, John; Restifo, Nicholas P.; Berzofsky, Jay A.; Leonard, Warren J.

doi:10.1084/jem.20041057

Cited by 654 publications

(611 citation statements)

References 36 publications

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“…This suggested that the IL-21 was acting through a CD8 T cell-dependent mechanism. Most recently, IL-21 has been reported to act synergistically with IL-15 to directly promote Ag-independent clonal expansion of CD44 high and CD44 low CD8 T cells (23). The same authors also observed a marked defect in Ag-specific CD8 T cell cytolytic activity after response to viral challenge in IL-21R Ϫ/Ϫ mice.…”

Section: Il-21 Promotes Differentiation Of Naive Cd8 T Cells To a Unisupporting

confidence: 54%

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IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

Casey

Mescher

2007

The Journal of Immunology

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IL-21, the most recently described member of the common γ-chain cytokine family, is produced by activated CD4 T cells, whereas CD8 T cells express the IL-21 receptor. To investigate a possible role for IL-21 in the priming of naive CD8 T cells, we examined responses of highly purified naive OT-I CD8 T cells to artificial APCs displaying Ag and B7-1 on their surface. We found that IL-21 enhanced OT-I clonal expansion and supported development of cytotoxic effector function. High levels of IL-2 did not support development of effector functions, but IL-2 was required for optimal responses in the presence of IL-21. IL-12 and IFN-α have previously been shown to support naive CD8 T cell differentiation and acquisition of effector functions through a STAT4-dependent mechanism. Here, we show that IL-21 does not require STAT4 to stimulate development of cytolytic activity. Furthermore, IL-21 fails to induce IFN-γ or IL-4 production and can partially block IL-12 induction of IFN-γ production. CD8 T cells that differentiate in response to IL-21 have a distinct surface marker expression pattern and are characterized as CD44high, PD-1low, CD25low, CD134low, and CD137low. Thus, IL-21 can provide a signal required by naive CD8 T cells to differentiate in response to Ag and costimulation, and the resulting effector cells represent a unique effector phenotype with highly effective cytolytic activity, but deficient capacity to secrete IFN-γ.

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Section: Il-21 Promotes Differentiation Of Naive Cd8 T Cells To a Unisupporting

confidence: 54%

“…2a); however, synergistic interactions have been reported for IL-21 and other IL-2 family members (19,23). Although we do not add exogenous IL-2 to the cultures, CD8 T cells are capable of transient autocrine IL-2 production upon activation (10,27,28).…”

Section: Optimal Il-21 Induction Of Cd8 T Cell Cytolytic Activity Reqmentioning

confidence: 99%

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

Casey

Mescher

2007

The Journal of Immunology

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“…Our findings show not only a higher proliferative potential of BM CMV-specific T cells but also the persistence of a specific T CM population upon in vitro expansion in the presence of IL-2 and IL-7. Ongoing studies focusing on conditions to more efficiently expand T CM by using cytokines, such as IL-15 and IL-21 [32], and depletion of regulatory T cells [33] hold promise for achieving the rapid generation of high frequencies of T CM for more efficient adoptive T cell therapy.…”

Section: Discussionmentioning

confidence: 99%

CMV‐specific central memory T cells reside in bone marrow

Letsch

Knödler

et al. 2007

Eur J Immunol

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CMV-specific CD8 + T cell responses in peripheral blood (PB) are characterized by a preponderance of effector and effector memory T cells. CMV-specific central memory T cells (T CM ), which are considered crucial in maintaining long-term immunity, are rarely detectable in PB. In this study we have analyzed differentiation and function of CMV pp65-specific CD8 + T cells in paired samples of human PB and BM using intracellular cytokine and tetramer staining. Overall frequencies of CMV pp65-specific T cells were similar in PB compared to BM; however, CMV-specific CD45RA -CCR7 + T CM were almost exclusively detectable in BM, which was not related to a general accumulation of T CM in BM. In vitro, CMV-specific T cells could be more efficiently expanded from BM (median 128-fold, n=6) than from PB (median 72-fold, p=0.01). Taken together, these data show that the BM is a compartment harboring CMV-specific T CM and underline the concept of the BM as a secondary immune organ. CMV specific BM-derived T CM might be a valuable source for generating T cells for adoptive transfer. IntroductionBased on phenotypic and functional characteristics two main populations of memory T cells can be distinguished: central memory T cells (T CM ), expressing the chemokine receptor CCR7, and effector memory T cells (T EM ), lacking lymph node homing receptors and migrating to peripheral tissues [1]. Both subsets can differentiate into effector T cells (T Eff ). The generally accepted concept holds that T CM have a higher proliferative potential and a greater capacity than T EM for long-lasting persistence in vivo [2][3][4].There is growing evidence suggesting that CD8 + T CM play a key role in long-term protection against acute infections in vivo [5][6][7]. In the chronic phase of persistent infections, differences in T cell differentiation were found dependent on viral specificity [8]. In general, specific CD8 + T cell responses against CMV and other chronic viral infections found in peripheral blood (PB) were CCR7 -belonging to T EM and T EFF [8][9][10][11]. It is unclear yet, whether the failure to detect CMV-specific CCR7 + T CM is related to the specific situation of chronic infection, where continuous stimulation of T cells occurs, or is due to their retention in lymphoid tissues. Information concerning the anatomical distribution of T cell differentiation subsets of virusspecific T cells in humans is very limited. In the study by Ellefsen et al.[10], however, several fold lower * These two authors contributed equally to this work. frequencies of CMV pp65-specific tetramer + CD8 + T cells were found in lymph nodes compared to PB. Recently the BM was identified as an important site for accumulation and proliferation of memory T cells [12][13][14]. Furthermore, there is growing evidence of the BM as secondary lymphoid organ priming naive T cells (T N ) and also efficiently stimulating memory T cells [15,16].In this study we comparatively analyzed the differentiation subsets of CMV pp65-specific CD8 + T cells in human PB and BM samples o...

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“…CD62L hi Tcm cells generated in the presence of IL-15 have been shown to eradicate large, established tumors after vaccination with a recombinant virus and administration of IL-2, while cells of a CD62L lo effector/Tem phenotype were ineffective [9]. Similarly, treatment with IL-15 and/or IL-21, factors that support the expansion of Tcm cells, led to improved anti-tumor activity [16][17][18]. Lowering the antigen concentration or reducing the culture duration also promoted the development of Tcm-like cells, which had reduced effector function but remained able to destroy established EG7 tumors [19].…”

Section: Discussionmentioning

confidence: 99%

Effector CD8⁺ T cells activated in vitro confer immediate and long‐term tumor protection in vivo

Perret

Ronchese

2008

Eur J Immunol

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We studied the ability of CD8 1 T cells activated in vitro to mediate tumor protection after transfer into adoptive hosts. TCR transgenic CD8 1 T cells were activated in culture with DC and specific peptide antigen, and briefly expanded in IL-2 containing medium. Cultured cells acquired a CD44 hi CD62L lo phenotype, and following in vivo transfer they preferentially homed to non-lymphoid tissues and spleen. In vivo, their numbers declined between day 0 and day 20, and then remained relatively stable from day 20 to day 90. Over time, many of the injected cells re-expressed CD62L, and acquired the ability to localize to secondary lymphoid organs. Transferred T cells underwent low-level proliferation, expressed IL-7Ra and IL-15Rb, were cytotoxic in vivo, and retained the ability to produce IL-2, IFN-c and TNF-a upon ex vivo restimulation. In addition, transferred T cells conferred a high degree of tumor protection, which was greatest immediately after injection, and remained significant even when tumor was given 90 days after T-cell transfer. We conclude that in vitro generated effector T cells can mediate immediate and long-term tumor protection, and develop into long-lived memory T-cell populations in vivo.

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Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function

Cited by 654 publications

References 36 publications

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

CMV‐specific central memory T cells reside in bone marrow

Effector CD8⁺ T cells activated in vitro confer immediate and long‐term tumor protection in vivo

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Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function

Cited by 654 publications

References 36 publications

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

CMV‐specific central memory T cells reside in bone marrow

Effector CD8+ T cells activated in vitro confer immediate and long‐term tumor protection in vivo

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Effector CD8⁺ T cells activated in vitro confer immediate and long‐term tumor protection in vivo