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INTERLEUKIN-7 DIFFERENTIALLY REGULATES THE ACTIVATION, PROLIFERATION, AND HOMING OF T-CELLS: IMPLICATIONS FOR IMMUNOTHERAPY

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Date Issued:
2010
Abstract/Description:
Interleukin-7 (IL-7) is an essential lymphocyte growth factor required for the survival and proliferation of mature T-cells. As a therapeutic agent, IL-7 has the potential to restore T-cell numbers following immune depletion and to promote immunity against cancers. While the survival function of IL-7 is well established, less is known about how it supports T-cell expansion, a critical feature of the immune response. To study the biological effects of IL-7 on T-cell growth, we developed an in vitro culture technique to expand T-cells ex vivo. A significant finding from our studies is that IL-7 did not induce the expansion of all T-cells, indicating that there are inherent differences in the response of individual T-cell subsets to IL-7. Culture with high doses of IL-7 (>150 ng/ml) preferentially expanded CD8 T-cells, but lead to the dramatic loss of CD4 T-cells which favored growth in lower dosages of IL-7 (<10 ng/ml). This effect was due to the regulation of LCK, a kinase predominantly associated with the CD4 co-receptor. We found that transgenic expression of the CD4 co-receptor onto CD8 T-cells promoted their growth in lower concentrations of IL-7. Conversely, inhibition of LCK activity in CD4 T-cells restored their responsiveness to high doses of IL-7 as indicated by the activation of the transcription factor STAT5, in a manner similar to CD8 T-cells. Interestingly, not all CD8 T-cells expanded in high doses of IL-7 and this effect was specific to CD8 T-cells that expressed an activated memory phenotype. We found that IL-7 promoted the proliferation of CD8 T-cells through Cdc25A, a phosphatase required for cell cycle progression. Expression of a constitutively active Cdc25A could maintain T-cell survival and proliferation in the absence of IL-7, demonstrating that Cdc25A is a crucial transducer of IL-7 growth signals. Inhibition of Cdc25A was sufficient to decrease proliferation and down-regulate the expression of activation/ memory markers on CD8 T-cells in the presence of IL-7. Upon further study, we identified a novel role for IL-7 through Cdc25A in the regulation of CD62L, an adhesion molecule required for lymph node entry. Culture with high doses of IL-7 down-regulated the expression of CD62L, suggesting that high doses of IL-7 could affect the ability of T-cells to enter or re-enter the lymph nodes. Collectively, our findings demonstrate that IL-7 administration at the supraphysiological doses currently used in the clinical trials could have a negative impact on the growth of CD4 T-cells and the homing of CD8 T-cells to the lymph nodes, effects which can impede the generation of an effective immune response.
Title: INTERLEUKIN-7 DIFFERENTIALLY REGULATES THE ACTIVATION, PROLIFERATION, AND HOMING OF T-CELLS: IMPLICATIONS FOR IMMUNOTHERAPY.
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Name(s): Kittipatarin, Christina, Author
Khaled, Annette, Committee Chair
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2010
Publisher: University of Central Florida
Language(s): English
Abstract/Description: Interleukin-7 (IL-7) is an essential lymphocyte growth factor required for the survival and proliferation of mature T-cells. As a therapeutic agent, IL-7 has the potential to restore T-cell numbers following immune depletion and to promote immunity against cancers. While the survival function of IL-7 is well established, less is known about how it supports T-cell expansion, a critical feature of the immune response. To study the biological effects of IL-7 on T-cell growth, we developed an in vitro culture technique to expand T-cells ex vivo. A significant finding from our studies is that IL-7 did not induce the expansion of all T-cells, indicating that there are inherent differences in the response of individual T-cell subsets to IL-7. Culture with high doses of IL-7 (>150 ng/ml) preferentially expanded CD8 T-cells, but lead to the dramatic loss of CD4 T-cells which favored growth in lower dosages of IL-7 (<10 ng/ml). This effect was due to the regulation of LCK, a kinase predominantly associated with the CD4 co-receptor. We found that transgenic expression of the CD4 co-receptor onto CD8 T-cells promoted their growth in lower concentrations of IL-7. Conversely, inhibition of LCK activity in CD4 T-cells restored their responsiveness to high doses of IL-7 as indicated by the activation of the transcription factor STAT5, in a manner similar to CD8 T-cells. Interestingly, not all CD8 T-cells expanded in high doses of IL-7 and this effect was specific to CD8 T-cells that expressed an activated memory phenotype. We found that IL-7 promoted the proliferation of CD8 T-cells through Cdc25A, a phosphatase required for cell cycle progression. Expression of a constitutively active Cdc25A could maintain T-cell survival and proliferation in the absence of IL-7, demonstrating that Cdc25A is a crucial transducer of IL-7 growth signals. Inhibition of Cdc25A was sufficient to decrease proliferation and down-regulate the expression of activation/ memory markers on CD8 T-cells in the presence of IL-7. Upon further study, we identified a novel role for IL-7 through Cdc25A in the regulation of CD62L, an adhesion molecule required for lymph node entry. Culture with high doses of IL-7 down-regulated the expression of CD62L, suggesting that high doses of IL-7 could affect the ability of T-cells to enter or re-enter the lymph nodes. Collectively, our findings demonstrate that IL-7 administration at the supraphysiological doses currently used in the clinical trials could have a negative impact on the growth of CD4 T-cells and the homing of CD8 T-cells to the lymph nodes, effects which can impede the generation of an effective immune response.
Identifier: CFE0003372 (IID), ucf:48449 (fedora)
Note(s): 2010-08-01
Ph.D.
Medicine, Department of Biomolecular Science
Masters
This record was generated from author submitted information.
Subject(s): cytokine
lymphocytes
proliferation
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0003372
Restrictions on Access: campus 2015-07-01
Host Institution: UCF

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