Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells

Seddon, Benedict; Tomlinson, Peter; Zamoyska, Rose

doi:10.1038/ni946

Cited by 415 publications

(377 citation statements)

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“…1). A number of different cytokines, particularly IL-7 and IL-15, have been reported to be required for survival and maintenance of memory T cells in vivo [26,27,29,30]. In our model system, IL-2 is the only exogenously added cytokine.…”

Section: Discussionmentioning

confidence: 99%

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In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

et al. 2006

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An adaptive immune response implies expansion of activated T cells and subsequent elimination to maintain homeostasis in a process called activation-induced cell death. Some cells, however, differentiate into memory cells and ensure a strong secondary immune response. To analyze the apoptosis phenotype of memory T cells on a cellular and molecular level, we have established an in vitro model of T cell activation and generation of cells phenotypically and functionally similar to memory cells. These longterm cultured T cells show a CD95-resistant phenotype, although they are still sensitive towards TCR/CD3-mediated apoptosis. Biochemical analysis revealed that these cells shift from CD95 type I (direct signaling from the receptor) during the effector phase to CD95 type II cells (dependent on the mitochondrial amplification loop). Moreover, their mitochondria are protected, probably due to high expression levels of Bcl-x L and Bcl-2. Thus, our data suggest a mechanism how memory T cells acquire resistance towards bystander cell death via the CD95 system.

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Section: Discussionmentioning

confidence: 99%

“…In addition, IL-7 was also shown to promote homeostatic proliferation in CD8 T cells [29]. Recently, it has been shown that IL-7, but not IL-15, is required for the maintenance of CD4 memory T cells [27,30].…”

Section: Introductionmentioning

confidence: 99%

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

et al. 2006

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“…The prevailing concept of how circulating antigen‐experienced T lymphocytes are maintained is that of homeostatic proliferation, driven by cytokines, replacing memory T cells which die either due to a limited intrinsic half‐life, or by neglect, not being able to secure sufficient survival stimuli. The concept has been detailed out in a review by Surh and Sprent,94 summarizing evidence that interleukin‐15 is an essential cytokine for the maintenance of CD8 + memory T cells,95 while maintenance of CD4 + memory T cells is dependent more on IL‐7 than on IL‐15 96, 97. T‐cell receptor signaling seems not to be important for the maintenance of CD4 + memory T cells.…”

Section: The Lifestyle Of Circulating Memory T Lymphocytesmentioning

confidence: 99%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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SummaryMemory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic “half‐lives”, but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.

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“…IL-2 and IL-15 can also support memory cell division and have been used in combination with Ag-driven stimulation, for the expansion of CTL [24][25][26][27][28][29]. 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].…”

mentioning

confidence: 99%

“…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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Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells

Cited by 415 publications

References 41 publications

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

Immunological memories of the bone marrow

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

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Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells

Cited by 415 publications

References 41 publications

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

Immunological memories of the bone marrow

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