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Generation in T Cell Proliferation and Memory Differing Roles Of Differing Roles of Inflammation and Antigen in T Cell Proliferation and Memory Generation This information is current as Dirk H. Busch, Kristen M. Kerksiek and Eric G. Pamer of September 23, 2021. J Immunol 2000; 164:4063-4070; ; doi: 10.4049/jimmunol.164.8.4063 http://www.jimmunol.org/content/164/8/4063 Downloaded from References This article cites 44 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/164/8/4063.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Differing Roles of Inflammation and Antigen in T Cell Proliferation and Memory Generation1 Dirk H. Busch,2 Kristen M. Kerksiek, and Eric G. Pamer3 Recent studies have demonstrated that viral and bacterial infections can induce dramatic in vivo expansion of Ag-specific T lymphocytes. Although presentation of Ag is critical for activation of naive T cells, it is less clear how dependent subsequent in vivo T cell proliferation and memory generation are upon Ag. We investigated T cell expansion and memory generation in mice infected alternately with strains of Listeria monocytogenes that contained or lacked an immunodominant, MHC class I-restricted T cell epitope. We found substantial differences in the responses of effector and memory T cells to inflammatory stimuli. Although effector T cells undergo in vivo expansion in response to bacterial infection in the absence of Ag, memory T cells show no evidence for such bystander activation. However, Ag-independent expansion of effector T cells does not result in increased memory T cell frequencies, indicating that Ag presentation is critical for effective memory T cell generation. Early reinfection of mice with L. Downloaded from monocytogenes before the maximal primary T cell response induces typical memory expansion, suggesting that the capacity for a memory T cell response exists within the primary effector population. Our findings demonstrate that T cell effector proliferation and memory generation are temporally overlapping processes with differing requirements for Ag. The Journal of Immunology, 2000, 164: 4063–4070. he innate and adaptive immune systems collaborate in cells is crucial for the development of effective protective immu- http://www.jimmunol.org/ mammalian defense against invasive pathogens, control- nity against many intracellular pathogens (2, 7). The similarity of T ling primary infections and rapidly eliminating pathogens memory and effector TCR repertoires suggests that memory T cells upon subsequent exposures. Protective immunity, which is medi- derive from effectors by a stochastic rather than selective mecha- ated by Ag-specific memory B and T lymphocytes, is rapidly ac- nism (8–12). Other studies also suggest that CD8ϩ memory T cells tivated after re-exposure to the pathogen and greatly limits the are posteffector T cells, although this has not been conclusively extent and pathology of infection. The in vivo processes that gen- demonstrated (1, 13). A recent study using an approach to “mark” erate and maintain protective immunity remain mysterious (1), and genes that have been transiently induced indicates that memory T fundamental questions regarding T cell memory remain unan- cells have a history of expressing genes associated with effector T swered. When are memory T cells generated during the course of cells. However, only a subset of effector T cells was maintained as by guest on September 23, 2021 primary infection? Are memory T cells generated during the pri- memory T cells, and these were detectable during primary infec- mary immune response, or do they develop during the T cell con- tion (14). These findings suggest that memory T cells represent a traction phase after clearance of the infection? Are in vivo T cell subset of the effector T cell population that is generated during the expansion and T cell memory generation tightly linked, or can acute, primary immune response. The mechanisms that promote these processes be dissociated? What is the role of Ag during in the development and expansion of early memory T cells and the vivo expansion of T cell populations and the generation of T cell factors that result in increased sensitivity and rapidity of memory memory? T cell activation (15, 16) remain unknown. ϩ CD8 CTL often play a major role in immunity to viral and The role of Ag during in vivo T cell expansion and memory T intracellular bacterial infections (2). CTL recognize pathogen-de- cell generation is poorly understood. Although Ag is required for rived peptide epitopes presented by MHC class I molecules on the T cell priming, long-term persistence of Ag-specific CD8ϩ mem- surface of infected cells (3, 4), resulting in cytolytic destruction of ory T cell populations is Ag-independent (17). Indeed, Ag-inde- the infected cell (5) and, potentially, direct killing of the pathogen pendent stimulation of memory T cell populations has been dis- ϩ (6). The generation and maintenance of specific CD8 memory T cussed as an important mechanisms for the maintenance of T cell memory (18). Recent studies demonstrate that memory T cells divide in the periphery in the absence of MHC molecules (19, 20), Sections of Infectious Diseases and Immunobiology, Yale University School of Med- providing further evidence for Ag-independent proliferation of icine, New Haven, CT 06511 Ag-specific memory T cells. Ag-independent “bystander” activa- Received for publication January 6, 2000. Accepted for publication February 7, 2000. tion of T lymphocytes has been proposed in the context of viral The costs of publication of this article were defrayed in part by the payment of page infections that induce massive populations of activated T lympho- charges. This article must therefore be hereby marked advertisement in accordance cytes, and the ability of type 1 IFN to play a role in this process has with 18 U.S.C. Section 1734 solely to indicate this fact. been demonstrated (21). However, more recent studies have dem- 1 This work was supported by National Institutes of Health Grants AI-33143 and AI-39031. D.H.B. was supported by a Howard Hughes Medical Institute Research onstrated that most activated T cells after viral infection are Ag- Fellowship for Physicians. specific and that bystander activation accounts for few activated T 2 Current address: Institute for Microbiology, Immunology and Hygiene, Technical cells (22, 23). After in vivo T cell priming, Ag-specific T cell University Munich, Trogerstra␤e 24, 81675 Munich, Germany populations expand, plateau, and then contract into long-term 3 Address correspondence and reprint requests to Dr. Eric G. Pamer, Sections of memory populations. The size of memory T cell populations cor- Infectious Diseases and Immunobiology, Yale University School of Medicine, Lab- oratory of Clinical Investigation 803, 333 Cedar Street, New Haven, CT 06520. E- relates with the T cell burst size (12, 24), suggesting that the pro- mail address: [email protected] cesses that drive in vivo T cell expansion also influence memory T Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 4064 INFLAMMATION AND T CELL MEMORY FIGURE 1. Synchronous in vivo T cell kinet- ics of H2-Kd-restricted T cell populations during primary and recall infection with L. monocyto- genes. A group of age-matched female BALB/c mice was infected with 2000 L. monocytogenes (L.m.) 10403s i.v. (day 0). At the indicated times after infection, the number of viable bacteria in the spleen was determined as indicated in Mate- rials and Methods. The size of LLO91–99- and p60217–225-specific T cell population was deter- mined by flow cytometry using H2-Kd tetramers. Absolute numbers of Ag-specific T cells were calculated on the basis of their frequency and the total number of splenocytes. A subgroup of mice received a second i.v. injection of 100,000 L. monocytogenes 5 wk after primary infection. Mean values and SD for two mice per time point are plotted. Filled bars, viable bacteria per E Downloaded from spleen; , LLO91–99-specific T cells per spleen; Ⅺ , p60217–225-specific T cells per spleen. cell development. The relative importance of pathogen-derived Ag infectious systems, we do not find evidence for Ag-independent http://www.jimmunol.org/ presentation as opposed to infection-induced inflammation in de- bystander activation of memory T cell populations. These studies termining in vivo T cell expansion kinetics and memory generation demonstrate that in vivo expansion of Ag-specific effector T cell is unknown. Although some studies indicate that Ag-independent populations can be promoted by multiple factors but that the pres- expansion may be an important feature of in vivo T cell responses ence of Ag is critical for the generation of memory T cells. (25), direct evidence for this is lacking. We have used murine infection with Listeria monocytogenes to study pathogen-specific T cell responses in vivo. Mice infected i.v. Materials and Methods with a sublethal dose of this Gram-positive, intracellular bacterium Mice and bacteria by guest on September 23, 2021 rapidly clear the pathogen and develop long-lasting immunity, which is predominantly mediated by CD8ϩ T cells (26, 27).
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