Modeling of Influenza-Specific CD8+ T Cells during the Primary Response Indicates that the Spleen Is a Major Source of Effectors This information is current as Hulin Wu, Arun Kumar, Hongyu Miao, Jeanne of October 1, 2021. Holden-Wiltse, Timothy R. Mosmann, Alexandra M. Livingstone, Gabrielle T. Belz, Alan S. Perelson, Martin S. Zand and David J. Topham J Immunol 2011; 187:4474-4482; Prepublished online 23 September 2011; doi: 10.4049/jimmunol.1101443 Downloaded from http://www.jimmunol.org/content/187/9/4474 References This article cites 61 articles, 34 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/187/9/4474.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! 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The Journal of Immunology Modeling of Influenza-Specific CD8+ T Cells during the Primary Response Indicates that the Spleen Is a Major Source of Effectors Hulin Wu,*,1 Arun Kumar,*,1 Hongyu Miao,*,1 Jeanne Holden-Wiltse,* Timothy R. Mosmann,†,‡ Alexandra M. Livingstone,†,‡ Gabrielle T. Belz,x Alan S. Perelson,{ Martin S. Zand,{ and David J. Topham†,‡ The biological parameters that determine the distribution of virus-specific CD8+ T cells during influenza infection are not all directly measurable by experimental techniques but can be inferred through mathematical modeling. Mechanistic and semi- mechanistic ordinary differential equations were developed to describe the expansion, trafficking, and disappearance of activated virus-specific CD8+ T cells in lymph nodes, spleens, and lungs of mice during primary influenza A infection. An intensive sampling Downloaded from of virus-specific CD8+ T cells from these three compartments was used to inform the models. Rigorous statistical fitting of the models to the experimental data allowed estimation of important biological parameters. Although the draining lymph node is the first tissue in which Ag-specific CD8+ T cells are detected, it was found that the spleen contributes the greatest number of effector CD8+ T cells to the lung, with rates of expansion and migration that exceeded those of the draining lymph node. In addition, models that were based on the number and kinetics of professional APCs fit the data better than those based on viral load, suggesting that the immune response is limited by Ag presentation rather than the amount of virus. Modeling also suggests that http://www.jimmunol.org/ loss of effector T cells from the lung is significant and time dependent, increasing toward the end of the acute response. Together, these efforts provide a better understanding of the primary CD8+ T cell response to influenza infection, changing the view that the spleen plays a minor role in the primary immune response. The Journal of Immunology, 2011, 187: 4474–4482. urrent strategies for preventing or decreasing the sever- served antigenic regions in the viruses are perhaps the most im- ity of influenza infection focus on increasing virus- portant immune component against emerging novel strains of the C neutralizing Ab titers through vaccination, as experi- virus. Understanding the factors that regulate the T cell response is ence indicates that this is the best way to prevent morbidity and key to the development of new immunization strategies designed mortality. It is generally accepted that T cells provide a substantial to promote cross-reactive immunity. by guest on October 1, 2021 degree of protection from disease, and cytotoxic CD8+ T cells With the exception of certain highly pathogenic strains of in- control the infection by eliminating infected cells when neutral- fluenza (4–6), the virus infection is usually restricted to the air- izing Abs are absent (1–3). Because influenza viruses are unique ways and lung tissues. This phenomenon is believed to be due to in their ability to undergo antigenic shift, resulting in a wholesale the limited expression of host enzymes required to cleave the viral evasion of neutralizing Abs, T cells that cross-react with con- hemagglutinin protein into its active conformation (7, 8). Because of this, it takes time for Ag (and APCs) to reach the draining + *Department of Biostatistics and Computational Biology, University of Rochester lymph node (9, 10) and also for virus-specific effector CD8 Medical Center, Rochester, NY 14642; †David H. Smith Center for Vaccine Biology T cells to migrate through the bloodstream back to the site of and Immunology, University of Rochester Medical Center, Rochester, NY 14642; ‡Department of Microbiology and Immunology, University of Rochester Medical infection. The dynamic nature of this process makes it very dif- Center, Rochester, NY 14642; xDivision of Molecular Immunology, Walter and Eliza ficult to study directly. Conventional approaches rely on tissue { Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia; Theoret- sampling at defined time points to assemble a set of “snapshots” ical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545; and ‖Division of Nephrology, Department of Medicine, University of that can be linked together to understand the system as a whole. Rochester Medical Center, Rochester, NY 14642 Unfortunately, this understanding still depends on a number of 1H.W., A.K., and H.M. contributed equally to this work. assumptions. For example, a given tissue sampling tells us where Received for publication May 16, 2011. Accepted for publication August 23, 2011. the cells are at that point in time but does not reveal where they This work was supported by National Institute of Allergy and Infectious Diseases came from. In addition, the rates of cell proliferation and traf- Contract HHSN272201000055C and Grant R01 AI069351 (to M.S.Z.). Portions of ficking into and out of a given tissue can, at best, be inferred. In this work were performed under the auspices of the U.S. Department of Energy under Contract DE-AC52-679 06NA25396 (to A.S.P.). the end, the number of cells at any single tissue site will depend on Address correspondence and reprint requests to Dr. Martin S. Zand or Dr. David the combined, simultaneous processes of proliferation, trafficking, J. Topham, University of Rochester Medical Center, 601 Elmwood Avenue, Box 675, retention, and cell loss due to death, phagocytosis, or sloughing. Rochester, NY 14642 (M.Z.) or University of Rochester Medical Center, 601 Elmwood Mathematical modeling and computational approaches to the Avenue, Box 609, Rochester, NY 14642 (D.J.T.). E-mail addresses: martin_zand@ urmc.rochester.edu (M.Z.) and [email protected] (D.J.T.) problem offer one of the best means to estimate the key biological Abbreviations used in this article: AIC, Akaike Information Criterion; cMEM, com- parameters that cannot be directly and unambiguously measured. plete minimum essential medium; DC, dendritic cell; IAV, influenza A virus; MLN, Mathematical models have long been used to investigate viral dy- mediastinal lymph node; NP, nucleoprotein; ODE, ordinary differential equation; PA, namics and immune responses to viral infections, including influenza acid polymerase; RSS, residual sum of squares. A virus (IAV) (11–18). In particular, we recently developed complex Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 differential equation models to quantify key kinetic parameters and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1101443 The Journal of Immunology 4475 predict early and adaptive immune responses against IAV infection draining lymph nodes were digested for 20 min at room temperature with (19, 20). However, limited by available experimental information, collagenase/DNase and then treated for 5 min with EDTA to disrupt our previous studies mainly focused on the lung. Better under- T cell–dendritic cell (DC) complexes. Previously, it has been shown that depletion of cells expressing CD11c removed Ag-specific stimulatory standing of immune cell kinetics among multiple compartments is capacity indicating that Ag presentation was limited to CD11c+ DCs thus a natural and necessary next step. Toward this goal, in this (9, 22). The LacZ-inducible hybridomas specific for Db nucleoprotein b article we propose new mathematical models of multicompartment (NP)366–374 (BWZ-IFA.NP4) (9) and D acid polymerase (PA)224–233 cell trafficking and fit them to experimental data from mice infected (BWZ-IFA.PA1) were maintained in DMEM containing 10% FCS, 50 mM 2-mercaptoethanol, 2 mM L-glutamine, 100 U/ml penicillin, and 100 mg/ with the H3N2 influenza A/X31 strain. Based on model fitting re- ml streptomycin (hybridoma medium). These clones were used to analyze sults, we compare and verify several mechanistic hypotheses that Ag presentation by lymph node cells, as previously described (23). cannot