Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells

Kaech, Susan M.; Tan, Joyce T.; Wherry, E. John; Konieczny, Bogumila T.; Surh, Charles D.; Ahmed, Rafi

doi:10.1038/ni1009

Cited by 1,643 publications

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“…1,14,33 KLRG1 lo CD127 hi cells are more protected from death because they express increased levels of Bcl-2, as genetic loss or pharmacologic inhibition of Bcl-2 enhanced their Bimdriven death. 33,43 Further, we have shown that a common g chain cytokine/STAT5/Bcl-2 network acts downstream of IL-7 and IL-15 to protect KLRG1 lo CD127 hi effector T cells from Bim and likely Puma, favoring memory cell development. 34 Third, as mentioned above, the massive expansion of effector and pre-memory subsets in Bim À / À mice severely restricts IL-15 availability for KLRG1 hi CD127 lo cells.…”

Section: Discussionmentioning

confidence: 96%

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Kurtuluş

Sholl

et al. 2014

Cell Death Differ

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During the effector CD8 þ T-cell response, transcriptional differentiation programs are engaged that promote effector T cells with varying memory potential. Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, it is unclear if the lack of cell death enhances memory. Here, we investigated effector CD8 þ T-cell fate in mice whose death program has been largely disabled because of the loss of Bim. Interestingly, the absence of Bim resulted in a significant enhancement of effector CD8 þ T cells with more memory potential. Bim-driven control of memory T-cell development required T-cell-specific, but not dendritic cell-specific, expression of Bim. Both total and T-cell-specific loss of Bim promoted skewing toward memory precursors, by enhancing the survival of memory precursors, and limiting the availability of IL-15. Decreased IL-15 availability in Bim-deficient mice facilitated the elimination of cells with less memory potential via the additional pro-apoptotic molecules Noxa and Puma. Combined, these data show that Bim controls memory development by limiting the survival of pre-memory effector cells. Further, by preventing the consumption of IL-15, Bim limits the role of Noxa and Puma in causing the death of effector cells with less memory potential.

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Section: Discussionmentioning

confidence: 96%

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Kurtuluş

Sholl

et al. 2014

Cell Death Differ

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“…The pool of effector CD8 T cells consists of two subsets; the majority (95%) are terminal effectors (TE) that are destined to die and the minority (5%) subset of effector cells, termed memory precursors (MP), survive to give rise to the pool of long-lived memory T cells 5 . These two subsets can be distinguished on the basis of their expression of cell surface markers Klrg1 and CD127 10–12 . So, we analyzed the TE and MP effector subsets at day 8 and quite strikingly both subsets were equally methylated at the CD62L promoter region and they also expressed low levels of CD62L message (Fig.1d, Extended data 1f,1g).…”

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confidence: 99%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

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381

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Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These resting memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogen, but also have many properties in common with naïve cells, including the ability to migrate to lymph nodes and spleen, and their pluri-potency. Thus, memory cells embody features of both naïve and effector cells, fueling a long-standing debate centered on whether memory T cells develop from effector cells or directly from naïve cells1–4. To better define the developmental path of memory CD8 T cells we investigated changes in DNA methylation programming at naïve and effector genes in virus specific CD8 T cells during acute LCMV infection of mice. Methylation profiling of effector CD8 T cell subsets at day 4 and 8 after infection showed that, rather than retaining a naïve epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naïve-associated genes and became demethylated at loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase, Dnmt3a, at an early stage of effector differentiation strikingly reduced methylation of naïve-associated genes and resulted in faster re-expression of these naïve genes, accelerating memory cell development. Longitudinal phenotypic and epigenetic characterization of virus-specific memory-precursor CD8 T cells transferred into antigen-free mice revealed that their differentiation into memory cells was coupled to cell-division independent erasure of de novo methylation programs and re-expression of naïve-associated genes. These data provide evidence that epigenetic repression of naïve-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells supporting a differentiation model where memory T cells arise from a subset of fate-permissive effector T cells.

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“…IL-7 regulates peripheral T-cell homeostasis, and contributes to the generation and long-term survival of both CD4 1 and CD8 1 memory T lymphocytes in vivo [30,31]. In some cases IL-7 amplifies Agdriven T-cell responses [32][33][34][35][36], favors the transition of effector to memory cells [31,[37][38][39], and sustains a slow, homeostaticlike, Ag-independent memory T-cell proliferation [24,30,40]. Furthermore, its administration at the time of Ag withdrawal supports memory CD8 1 T-cell generation [41], and enhances vaccine-mediated immunity when provided in adjuvant settings [42,43].…”

mentioning

confidence: 99%

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells

Caserta

Alessi²,

Basso³

et al. 2010

Eur J Immunol

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It is well established that tumours hinder both natural and vaccine-induced tumourspecific CD4 1 T-cell responses. Adoptive T-cell therapy has the potential to circumvent functional tolerance and enhance anti-tumour protective responses. While protocols suitable for the expansion of cytotoxic CD8 1 T cells are currently available, data on tumour-specific CD4 1 T cells remain scarce. We report here that CD4 1 T cells sensitized to tumour-associated Ag in vivo, proliferate in vitro in response to IL-7 without the need for exogenous Ag stimulation and accumulate several folds while preserving a memory-like phenotype. Both cell proliferation and survival accounts for the outgrowth of tumoursensitized T cells among other memory and naive lymphocytes following exposure to IL-7. Also IL-2, previously used to expand anti-tumour CTL, promotes tumour-specific CD4 1 T-cell accumulation. However, IL-7 is superior to IL-2 at preserving lymphocyte viability, in vitro and in vivo, maintaining those properties, that are required by helper CD4 1 T cells to confer therapeutic efficacy upon transplantation in tumour-bearing hosts. Together our data support a unique role for IL-7 in retrieving memory-like CD4 1 T cells suitable for adoptive T-cell therapy.Key words: Adoptive T-cell therapy . Cytokines . T helper cells . Tumour immunology Supporting Information available online IntroductionAdoptive cell therapy (ACT) with tumour-specific CD8 1 T lymphocytes has become one of the most promising approaches in cancer therapy. Rosenberg et al. first demonstrated the possibility to expand tumour-specific cytotoxic CD8 1 lymphocytes (CTL) from tumour lesions in high doses of IL-2 [1]. These authors later showed that the state of lymphocyte differentiation, induced in the presence of common g-chain receptor cytokines, is critical for therapeutic efficacy [2,3]. In spite of the recognized importance of Ag-specific CD4 1 T cells in both adaptive and innate immune responses, their identification remains elusive, and their in vitro amplification is hindered by the absence of reliable protocols able to support cell proliferation in the absence of terminal differentiation. While, Ag tumours elicit natural tumour-specific CD4 1 T-cell responses [4][5][6][7][8][9][10], functional tolerance is eventually observed through the induction of T-cell anergy [11,12], T-cell depletion [13] or the limitation of the memory repertoire [10,14,15]. This is possibly due to Ag persistence, and continual TCR signaling, as in the case of chronic 470viral infections [16][17][18]. In addition, regulatory CD4 1 T cells have been frequently found in the case of tumours, often among the tumour-infiltrating lymphocytes, thereby persuading the general interest towards CD8 1 CTL. Thus, CD4 1 T cells have not been widely exploited in ACT as well as the properties (i.e. homing potential, functionality, and survival) that CD4 1 T cells might require for successful applications in ACT are much less known than in the case for CD8 1 CTL.A large, still not definitive, amount of ...

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Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells

Cited by 1,643 publications

References 47 publications

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Effector CD8 T cells dedifferentiate into long-lived memory cells

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells

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Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells

Cited by 1,643 publications

References 47 publications

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Effector CD8 T cells dedifferentiate into long-lived memory cells

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4+ T cells

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IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells