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Where do memory T cells come from?
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TRENDS in Molecular Medicine Vol.8 No.11 November 2002
509
Journal Club
Where do memory T cells come from? Immunological memory provides a cellular recall mechanism for the rapid and efficient mobilization of the immune system against previously encountered pathogens. During a primary immune response to new pathogens or antigens, naive T cells are activated, and undergo proliferative expansion and differentiation into effector cells. Although most effector cells die after antigen clearance, some persist as memory T cells. The identity and functional properties of the effector cells that survive as memory T cells, as against those that perish, are not known. Furthermore, there are two types of effector CD4 T cells, distinguished by the cytokines they secrete: Th1 cells produce interferon-γ (IFN-γ), whereas Th2 cells produce interleukin-4 (IL-4). It is not known whether these two cell types have similar capacities for memory-cell generation. Seder and colleagues have begun to address these longstanding questions regarding memory T-cell generation in a recent intriguing study [1]. Using a combination of cytokine-capture techniques and in vivo adoptive transfers, they have demonstrated that the persisting memory
T-cell population derives from activated cells that are not producing IFN-γ. To do this, the authors generated antigen-specific Th1 effector cells, either in vitro or in vivo, from DO11.10 mice expressing a transgenic T-cell receptor specific for ovalbumin and MHC class II. They sorted the resultant Th1 population into IFN-γ + and IFN-γ − cells, and transferred these subsets into unmanipulated, syngeneic (genetically identical) mouse hosts. Several days post-transfer, they were able to detect transferred cells of both IFNγ+ and IFN-γ − types. However, after one week in the mouse hosts, the IFN-γ + cells were no longer evident in lymphoid and lung tissue, whereas IFN-γ − cells persisted. Although the investigators did not examine other tissues that might serve as reservoirs for effector T cells, such as the lamina propria of the gut, these results strongly suggest that the precursors of long-lived memory T cells reside in the IFN-γ − fraction of effector cells. The results also imply that once effector T cells have differentiated fully to produce IFN-γ, they cannot convert to long-lived memory T cells. Interestingly, the authors also noted that this survival dichotomy between cytokine
producers and non-producers does not occur with Th2 cells, for which the IL-4+ and IL-4− fractions have similar survival potentials in vivo. …development of memory is crucially ‘… dependent upon the type of response, the cytokines produced, and the differentiation state of activated cells.’ Hence, development of memory is crucially dependent upon the type of response, the cytokines produced, and the differentiation state of activated cells. These findings have profound implications for vaccine design, where it might be advantageous to establish conditions that do not promote full differentiation of Th1 effector cells, in order to promote a long-lived memory response. 1 Wu, C-Y. et al. (2002) Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo. Nat. Immunol. 3, 852–858
Donna Farber [email protected]
How retroviruses ensure expression of their genes Integration of viral DNA into the host genome is an important step in the retroviral lifecycle, and marks the point at which the virus loses control over its own lifecycle. The early steps, such as cell entry, reverse transcription and integration, are controlled mainly by viral enzymes. After integration, the proviral DNA is treated as a cellular gene and the cellular transcription machinery plays a major role in progression to the later steps of the viral lifecycle. Therefore, from the point of view of the virus, target-site selection is extremely important and determines the success of the infection. Despite this, retroviruses were believed to integrate more-or-less randomly into the genome. However, previous studies were limited by the fact that relatively few target sites were analyzed, and the recent publication of the human genome has provided a basis for studying the distribution of integration sites in more detail. http://tmm.trends.com
Schröder et al. [1] have performed such a study, investigating more than 500 integration sites derived from either HIV-1 or HIV-1-based vectors. They mapped and compared these integration sites with those of HIV-1 integration into naked DNA. A strong bias towards integration into transcription units was observed for cells infected in vivo, whereas integration sites in naked DNA were distributed according to relative proportion in the genome. Although, in this study, no functional class of genes was favoured as a target site, integration did correlate with transcriptional activity. Furthermore, the average expression level of potential target genes increased after infection. In addition to the bias towards transcriptionally active sites, regional hotspots for integration were identified. Also, HIV-1 rarely integrated into human endogenous retroviruses (HERVs), a finding that accords with the
predominant occurrence of HERVs in intergenic regions. From the point of view of the virus, this bias towards transcriptionally active sites makes sense, as it increases the likelihood of expression of the proviral DNA. One possible mechanism for the reported bias is a direct interaction between the viral pre-integration complex and proteins from the transcription machinery. Alternatively, the increased accessibility of chromatin in transcribed regions might be responsible. The elucidation of the exact mechanism will provide a basis for development of safer retroviral vectors, and might be the first step towards targeted retroviral integration. 1 Schröder, A.R.W. et al. (2002) HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110, 521–529
Dieter Klein [email protected]
1471-4914/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
TRENDS in Molecular Medicine Vol.8 No.11 November 2002
509
Journal Club
Where do memory T cells come from? Immunological memory provides a cellular recall mechanism for the rapid and efficient mobilization of the immune system against previously encountered pathogens. During a primary immune response to new pathogens or antigens, naive T cells are activated, and undergo proliferative expansion and differentiation into effector cells. Although most effector cells die after antigen clearance, some persist as memory T cells. The identity and functional properties of the effector cells that survive as memory T cells, as against those that perish, are not known. Furthermore, there are two types of effector CD4 T cells, distinguished by the cytokines they secrete: Th1 cells produce interferon-γ (IFN-γ), whereas Th2 cells produce interleukin-4 (IL-4). It is not known whether these two cell types have similar capacities for memory-cell generation. Seder and colleagues have begun to address these longstanding questions regarding memory T-cell generation in a recent intriguing study [1]. Using a combination of cytokine-capture techniques and in vivo adoptive transfers, they have demonstrated that the persisting memory
T-cell population derives from activated cells that are not producing IFN-γ. To do this, the authors generated antigen-specific Th1 effector cells, either in vitro or in vivo, from DO11.10 mice expressing a transgenic T-cell receptor specific for ovalbumin and MHC class II. They sorted the resultant Th1 population into IFN-γ + and IFN-γ − cells, and transferred these subsets into unmanipulated, syngeneic (genetically identical) mouse hosts. Several days post-transfer, they were able to detect transferred cells of both IFNγ+ and IFN-γ − types. However, after one week in the mouse hosts, the IFN-γ + cells were no longer evident in lymphoid and lung tissue, whereas IFN-γ − cells persisted. Although the investigators did not examine other tissues that might serve as reservoirs for effector T cells, such as the lamina propria of the gut, these results strongly suggest that the precursors of long-lived memory T cells reside in the IFN-γ − fraction of effector cells. The results also imply that once effector T cells have differentiated fully to produce IFN-γ, they cannot convert to long-lived memory T cells. Interestingly, the authors also noted that this survival dichotomy between cytokine
producers and non-producers does not occur with Th2 cells, for which the IL-4+ and IL-4− fractions have similar survival potentials in vivo. …development of memory is crucially ‘… dependent upon the type of response, the cytokines produced, and the differentiation state of activated cells.’ Hence, development of memory is crucially dependent upon the type of response, the cytokines produced, and the differentiation state of activated cells. These findings have profound implications for vaccine design, where it might be advantageous to establish conditions that do not promote full differentiation of Th1 effector cells, in order to promote a long-lived memory response. 1 Wu, C-Y. et al. (2002) Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo. Nat. Immunol. 3, 852–858
Donna Farber [email protected]
How retroviruses ensure expression of their genes Integration of viral DNA into the host genome is an important step in the retroviral lifecycle, and marks the point at which the virus loses control over its own lifecycle. The early steps, such as cell entry, reverse transcription and integration, are controlled mainly by viral enzymes. After integration, the proviral DNA is treated as a cellular gene and the cellular transcription machinery plays a major role in progression to the later steps of the viral lifecycle. Therefore, from the point of view of the virus, target-site selection is extremely important and determines the success of the infection. Despite this, retroviruses were believed to integrate more-or-less randomly into the genome. However, previous studies were limited by the fact that relatively few target sites were analyzed, and the recent publication of the human genome has provided a basis for studying the distribution of integration sites in more detail. http://tmm.trends.com
Schröder et al. [1] have performed such a study, investigating more than 500 integration sites derived from either HIV-1 or HIV-1-based vectors. They mapped and compared these integration sites with those of HIV-1 integration into naked DNA. A strong bias towards integration into transcription units was observed for cells infected in vivo, whereas integration sites in naked DNA were distributed according to relative proportion in the genome. Although, in this study, no functional class of genes was favoured as a target site, integration did correlate with transcriptional activity. Furthermore, the average expression level of potential target genes increased after infection. In addition to the bias towards transcriptionally active sites, regional hotspots for integration were identified. Also, HIV-1 rarely integrated into human endogenous retroviruses (HERVs), a finding that accords with the
predominant occurrence of HERVs in intergenic regions. From the point of view of the virus, this bias towards transcriptionally active sites makes sense, as it increases the likelihood of expression of the proviral DNA. One possible mechanism for the reported bias is a direct interaction between the viral pre-integration complex and proteins from the transcription machinery. Alternatively, the increased accessibility of chromatin in transcribed regions might be responsible. The elucidation of the exact mechanism will provide a basis for development of safer retroviral vectors, and might be the first step towards targeted retroviral integration. 1 Schröder, A.R.W. et al. (2002) HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110, 521–529
Dieter Klein [email protected]
1471-4914/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.