IL-7 is critical for homeostatic proliferation and survival of naïve T cells

Tan, Joyce T.; Dudl, Eric; Leroy, Éric; Murray, Richard M.; Sprent, Jonathan; Weinberg, Kenneth I.; Surh, Charles D.

doi:10.1073/pnas.161126098

Cited by 855 publications

(816 citation statements)

References 60 publications

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“…A similar need for trophic support also occurs in vitro [25][26][27]. Cell death is readily evident when T cells are cultured in media devoid of growth factors such as IL-2 [28][29][30]. To examine the sensitivity of peripheral CD4 cells to passive cell death, c-Maf Tg and non-Tg CD4 cells were cultured in complete medium without additional growth factors for 16 h. Cell death was assessed by flow cytometry using Annexin V and 7-amino-actinomycin D (7-AAD).…”

Section: Resultsmentioning

confidence: 99%

c‐Maf interacts with c‐Myb to down‐regulate Bcl‐2 expression and increase apoptosis in peripheral CD4 cells

et al. 2007

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The transcription factor c‐Maf is critical for IL‐4 production and the development of Th2 cells, which promote humoral immunity and protect against extracellular parasites. Yet, little else is known of c‐Maf function in CD4 cells. Here, we identify a novel role for c‐Maf in regulating susceptibility to apoptosis. Overexpression of c‐Maf results in increased susceptibility of CD4 cells to apoptosis induced by multiple stimuli, including growth factor withdrawal, dexamethasone, irradiation, and TCR engagement. This effect is independent of Fas or p53; however, Bcl‐2 expression is reduced in c‐Maf Tg CD4 cells. Immunoprecipitation and Western blot analyses demonstrate that c‐Maf–c‐Myb complex formation is enhanced among T cells from c‐Maf Tg mice compared to non‐Tg littermates following TCR engagement. Unlike non‐Tg T cells, c‐Myb binding to the Bcl‐2 promoter is not detectable in c‐Maf Tg T cells by chromatin immunoprecipitation. In reporter assays, Bcl‐2 promoter activity is reduced by c‐Maf in a dose‐dependent manner. Furthermore, transgene‐mediated Bcl‐2 expression corrects the apoptosis defect observed among c‐Maf Tg CD4 cells. These data suggest that c‐Maf can interact with c‐Myb to reduce Bcl‐2 expression, thereby limiting CD4 cell survival following TCR engagement.

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Section: Resultsmentioning

confidence: 99%

c‐Maf interacts with c‐Myb to down‐regulate Bcl‐2 expression and increase apoptosis in peripheral CD4 cells

et al. 2007

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“…In a therapeutic perspective, it is this memory subset which contains the fraction of interest, i.e., T cells which have already encountered the Ag and are therefore more suitable to be boosted or quenched, depending on the clinical setting. Although the preferential action of IL-7 on memory vs. naïve T cells is a matter of debate (Bielekova et al, 1999;Tan et al, 2001), the preferential targeting of the memory compartment could be more effective for IL-7 than for IL-2 or anti-CD28 mAb. As naïve T cells are more dependent on costimulation (Viglietta et al, 2002) and in light of the importance of both CD28 and IL-2 signals for Treg biology (Tang et al, 2003), these two regimens may actually exert their effect in the opposite direction, preferentially boosting HAL author manuscript inserm-00266553, version 1 13 naïve or Treg responses rather than memory/effector ones.…”

Section: Discussionmentioning

confidence: 99%

Serum-free culture medium and IL-7 costimulation increase the sensitivity of ELISpot detection

Martinuzzi

Scotto

Énée

et al. 2008

Journal of Immunological Methods

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Abbreviations: ANOVA, analysis of variance; CMV, cytomegalovirus; EBV, Epstein-Barr virus; GAD, glutamic acid decarboxylase; HS, human serum; IA-2, insulinoma-associated protein 2; IGRP, islet glucose-6-phosphatase catalytic subunit related protein; MP, matrix protein; PI, proinsulin; PPI, preproinsulin; SFC, spot-forming cells; T1D, type 1 diabetes. ABSTRACTThe identification of parameters maximizing detection sensitivity in ELISpot assays is important to transfer this technology into the clinical setting for identifying rare Ag-specific CD8 + T cells. We have therefore considered human IFN-Ȗ CD8 + T cell responses against viral epitopes to analyze different variables which could be critical during the epitope-specific stimulation period. Two parameters were found to greatly enhance detection sensitivity (i.e., to specifically increase epitope-driven signal while keeping background noise to a minimum):use of human serum-free vs. serum-supplemented culture medium (2.4-fold median increase) and addition of low dose IL-7 (1.5-fold increase). Incorporating both of these parameters into the ELISpot procedure proved capable of greatly amplifying (35.1-fold increase) the low grade CD8 + T cell responses directed against ȕ-cell epitopes of type 1 diabetes patients, as compared to a previously optimized procedure using human serum-supplemented medium and low dose IL-2. Implementation of this ELISpot procedure should expedite development of "immune staging" protocols for autoimmune as well as tumor and infectious diseases.

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“…The absence of IL-7 inhibits naïve CD4 + and CD8 + T-cell homeostatic proliferation and survival in a lymphopenic environment. The proliferation of donor cells in these IL-7 −/− hosts is rescued by the administration of exogenous IL-7 [36,41]. IL-7 has a significant role in naïve T-cell homeostatic proliferation but has little impact on memory T-cell expansion and survival in a lymphopenic host [37,38].…”

Section: Evidence For the Presence Of Homeostatic Cellular Cytokine 'mentioning

confidence: 99%

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

Klebanoff

Khong

Antony

et al. 2005

Trends in Immunology

411

288

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Lymphodepletion followed by adoptive cell transfer (ACT) of autologous, tumor-reactive T cells boosts antitumor immunotherapeutic activity in mouse and in humans. In the most recent clinical trials, lymphodepletion together with ACT has an objective response rate of 50% in patients with solid metastatic tumors. The mechanisms underlying this recent advance in cancer immunotherapy are beginning to be elucidated and include: the elimination of cellular cytokine 'sinks' for homeostatic γ C -cytokines, such as interleukin-7 (IL-7), IL-15 and possibly IL-21, which activate and expand tumor-reactive T cells; the impairment of CD4 + CD25 + regulatory T (Treg) cells that suppress tumorreactive T cells; and the induction of tumor apoptosis and necrosis in conjunction with antigenpresenting cell activation. Knowledge of these factors could be exploited therapeutically to improve the in vivo function of adoptively transferred, tumor-reactive T cells for the treatment of cancer.

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IL-7 is critical for homeostatic proliferation and survival of naïve T cells

Cited by 855 publications

References 60 publications

c‐Maf interacts with c‐Myb to down‐regulate Bcl‐2 expression and increase apoptosis in peripheral CD4 cells

c‐Maf interacts with c‐Myb to down‐regulate Bcl‐2 expression and increase apoptosis in peripheral CD4 cells

Serum-free culture medium and IL-7 costimulation increase the sensitivity of ELISpot detection

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

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