Effects of IL-7 on memory CD8+ T cell homeostasis are influenced by the timing of therapy in mice

Nanjappa, Som G.; Walent, Jane H.; Morre, Michel; Suresh, M.

doi:10.1172/jci32020

Cited by 58 publications

(77 citation statements)

References 55 publications

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“…By using this model, we found that TS/A tumours expressing LACK as an intracellular tumour-associated Ag (TS/A-LACK tumour cells) promote the expansion of short-lived LACK-specific effector-like CD4 1 T cells, while hinder the accumulation of both natural-and vaccine-induced central memory-like T cells [10,15]. As IL-7 is known to support memory CD4 1 T-cell expansion following Ag withdrawal [41], we asked whether this cytokine could be used in short-term in vitro cultures for the expansion of tumoursensitized CD4 1 T cells useful in ACT settings. In agreement with our previous findings, CD4 1 CD44 high T cells able to bind I-A d /LACK fluorescent multimers (Fig.…”

Section: Il-7 Favors the Accumulation Of Tumour-sensitized Cd4 1 T Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…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].Based on our previous results showing that tumours only allow a limited expansion of effector CD4 1 T cells, while hinder both natural and vaccine-induced memory-like cell responses [10,15], we attempted the ex vivo expansion of tumour-specific CD4 1 T cells to be used in ACT, using common-g-chain receptor cytokines. We report the ability of IL-7, rather than IL-2 in expanding tumour-sensitized T cells in short-term cultures, capable of sustaining anti-tumour protection in ACT settings.…”

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confidence: 99%

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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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Section: Il-7 Favors the Accumulation Of Tumour-sensitized Cd4 1 T Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Additionally, rIL-7 treatment during the contraction phase of the T-cell response increased Ag-specific memory CD8 1 T-cell proliferation and improved their function in mice [6]. It was recently demonstrated that IL-7 in combination with anti-IL-7 mAb significantly increased homeostatic T-cell expansion compared to IL-7 alone [7].…”

Section: Introductionmentioning

confidence: 99%

Marked enhancement of antigen‐specific T‐cell responses by IL‐7‐fused nonlytic, but not lytic, Fc as a genetic adjuvant

et al. 2010

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IL-7 plays a crucial role in the homeostatic proliferation, differentiation and survival of T cells, as well as in the survival and proliferation of precursor B cells. Here, we demonstrated that utilizing nonlytic Fc-fused IL-7 (IL-7-Fc m ) as a genetic adjuvant significantly enhanced not only CD4 1 but also CD8 1 T-cell responses by E7 DNA immunization, in addition to improving protection against TC-1-induced tumors in comparison to IL-7 alone. Similar results were obtained in OT-1 adoptive transfer experiments with OVA DNA injection, suggesting independence from antigenic nature and experimental conditions. In particular, the increased frequency of CD8 1 T cells was mainly due to enhanced T-cell proliferation in T-cell priming, and not to decreased cellular apoptosis. Interestingly, the enhanced adjuvant effect was not seen in the co-delivery of lytic Fc-fused IL-7 (IL-7-Fc) which increases T-cell apoptosis as well as T-cell proliferation, suggesting that the T-cell proliferative effect may be neutralized by T-cell apoptosis. Thus, our findings suggest that nonlytic Fc, in contrast to lytic Fc, fusion to cytokines may provide an insight in designing a potent genetic adjuvant for inducing CD4 1 and CD8 1 T-cell responses.

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“…In contrast to acute effector T cells, memory T cell populations are capable of prolonged persistence in the absence of antigenic stimulation through a process of homeostatic proliferation that is largely driven by in vivo exposure to IL-7 and IL-15 [20][21][22]. When melanoma tumors were inoculated into mice 60 days after LCMV infection, at which time remaining LCMV-specific T cells are of memory phenotype, populations of LCMV-specific memory T cells after 18 days of tumor growth (the same interval used in our previous experiments examining resting and acutely activated T cells) were no different than in tumor-free control mice.…”

Section: Discussionmentioning

confidence: 99%