Two papers in last week’s issue of Nature report that memory CD8 T cell responses can be enhanced by drugs that alter cellular metabolism. In one of the studies, the drug rapamycin – generally used as an immune suppressant – also accelerated the development of functional memory CD8 T cells. The findings may assist efforts to develop more effective CD8 T cell vaccines and therapeutics, because one of the inconvenient aspects of T cell biology is that the differentiation process by which naïve T cells become fully functional memory T cells takes time (several weeks in mice and considerably longer in people). Furthermore, restimulation of the T cells during this differentiation process can be counterproductive, reducing the quality of the resultant memory response.
On a somewhat similar theme, the new issue of Nature Medicine includes a paper showing that manipulation of the Wnt signaling pathway can also arrest the normal T cell differentiation process, leading to the generation of memory CD8 T cells with stem cell-like self-renewal properties.
Nature 460, 41-42 (2 July 2009) | doi:10.1038/460041a; Published online 1 July 2009
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Immunology: A metabolic switch to memory
Martin Prlic & Michael J. Bevan
Abstract
Two therapeutic drugs have been found to enhance memory in immune cells called T cells, apparently by altering cellular metabolism. Are changes in T-cell metabolism the key to generating long-lived immune memory?
Nature 460, 103-107 (2 July 2009) | doi:10.1038/nature08097; Received 23 January 2009; Accepted 23 April 2009; Published online 3 June 2009
Enhancing CD8 T-cell memory by modulating fatty acid metabolism
Erika L. Pearce1, Matthew C. Walsh1, Pedro J. Cejas1, Gretchen M. Harms1, Hao Shen2, Li-San Wang1,3, Russell G. Jones4 & Yongwon Choi1
1. Department of Pathology and Laboratory Medicine,
2. Department of Microbiology,
3. Penn Center for Bioinformatics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
4. McGill Cancer Centre, Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada
CD8 T cells, which have a crucial role in immunity to infection and cancer, are maintained in constant numbers, but on antigen stimulation undergo a developmental program characterized by distinct phases encompassing the expansion and then contraction of antigen-specific effector (TE) populations, followed by the persistence of long-lived memory (TM) cells Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to TM cells remain undefined. Here we show that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates CD8 TM-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 TE-cell responses, but have a profound defect in their ability to generate TM cells that is characterized by the disappearance of antigen-specific cells in the weeks after primary immunization. Microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lacking TRAF6 display defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and CD8 TM-cell generation in the absence of TRAF6. This treatment also increased CD8 TM cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.
Nature 460, 108-112 (2 July 2009) | doi:10.1038/nature08155; Received 27 April 2009; Accepted 15 May 2009; Published online 21 June 2009
mTOR regulates memory CD8 T-cell differentiation
Koichi Araki1, Alexandra P. Turner2, Virginia Oliva Shaffer2, Shivaprakash Gangappa2, Susanne A. Keller3, Martin F. Bachmann3, Christian P. Larsen2 & Rafi Ahmed1
1. Emory Vaccine Center and Department of Microbiology and Immunology,
2. Emory Transplant Center and Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA
3. Cytos Biotechnology AG, Wagistrasse 25, 8952 Zürich-Schlieren, Switzerland
Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.
Nature Medicine 15, 731 - 732 (2009), doi:10.1038/nm0709-731
Tumor immunotherapy: making an immortal army
Brent H. Koehn1 & Stephen P. Schoenberger1
Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Abstract
Manipulation of cell renewal pathways creates T memory stem cells that can generate a sustained and targeted immune response. These findings have broad implications for vaccine development and immunotherapy (pages 808–813).
Nature Medicine 15, 808 - 813 (2009)
Published online: 14 June 2009 | doi:10.1038/nm.1982
Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells
Luca Gattinoni1,2, Xiao-Song Zhong1,2, Douglas C Palmer1, Yun Ji1, Christian S Hinrichs1, Zhiya Yu1, Claudia Wrzesinski1, Andrea Boni1, Lydie Cassard1, Lindsay M Garvin1, Chrystal M Paulos1, Pawel Muranski1 & Nicholas P Restifo1
1. Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
2. These authors contributed equally to this work.
Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways1. The Wnt–-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation2, 3, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt–-catenin signaling by inhibitors of glycogen sythase kinase-3 or the Wnt protein family member Wnt3a arrested CD8+ T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44lowCD62LhighSca-1highCD122highBcl-2high self-renewing multipotent CD8+ memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8+ T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.
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