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De Novo Generation of CD4 T Cells Against Viruses Present in the Host During Immune Reconstitution

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De Novo Generation of CD4 T Cells Against Viruses Present in the Host During Immune Reconstitution IMMUNOBIOLOGY De novo generation of CD4 T cells against viruses present in the host during immune reconstitution Tomas Kalina, Hailing Lu, Zhao Zhao, Earl Blewett, Dirk P. Dittmer, Julie Randolph-Habecker, David G. Maloney, Robert G. Andrews, Hans-Peter Kiem, and Jan Storek T cells recognizing self-peptides are typi- Here we demonstrate in baboons infected gens present in the host. This finding cally deleted in the thymus by negative with baboon cytomegalovirus and ba- provides a strong rationale to improve selection. It is not known whether T cells boon lymphocryptovirus (Epstein-Barr vi- thymopoiesis in recipients of hematopoi- against persistent viruses (eg, herpesvi- rus–like virus) that after autologous trans- etic cell transplants and, perhaps, in other ruses) are generated by the thymus (de plantation of yellow fluorescent protein persons lacking de novo–generated CD4 novo) after the onset of the infection. (YFP)–marked hematopoietic cells, YFP؉ T cells, such as AIDS patients and elderly Peptides from such viruses might be con- CD4 T cells against these viruses were persons. (Blood. 2005;105:2410-2414) sidered by the thymus as self-peptides, generated de novo. Thus the thymus gen- and T cells specific for these peptides erates CD4 T cells against not only patho- might be deleted (negatively selected). gens absent from the host but also patho- © 2005 by The American Society of Hematology Introduction Patients who have undergone hematopoietic cell transplantation, disease in recipients of transplant (CMV pneumonia or gastroenteri- AIDS patients, patients with congenital thymic hypoplasia, and tis, EBV lymphoma).12,13 Seropositivity is a marker of infection elderly persons lack naive T cells because of insufficient generation because after primary infection of humans with human CMV or of T cells de novo (thymopoiesis).1-6 Ways to improve de novo EBV, anti-CMV/EBV antibodies are generated for life. In addition, generation have recently been studied using prothymopoietic the virus is always present in the infected human host—CMV in cytokines such as interleukin-7 (IL-7) or keratinocyte growth myeloid cells and EBV in B cells and pharyngeal epithelial cells.14 factor,7-9 thymic transplantation,5 or a thymic organoid (“artificial Baboon CMV (bCMV, SA6-like virus) and baboon lymphocrypto- thymus”).10 It is not known whether improved thymopoiesis might virus (bLCV, cercopithecine herpesvirus 12, herpesvirus papio) result in more T cells only for pathogens typically absent from the infections of baboons closely resemble CMV and EBV infections body (eg, neopathogens such as Ebola virus or cleared recall of humans.15-17 As do humans, baboons typically become infected pathogens such as measles virus) or for pathogens or malignant with bCMV and bLCV during childhood.18-20 bLCV can immortal- cells present in the body (eg, herpesviruses that infected the host ize baboon B cells as human EBV can immortalize human B before transplantation or the leukemia that necessitated hematopoi- cells,21 and similar genes are expressed in the immortalized B etic cell transplantation). The latter T cells may be more important, as cells.22 Baboon CMV genes are homologous and colinear with suggested by our recent study of 115 recipients of hematopoietic cell human CMV genes.19 Blewett’s team at Oklahoma State University transplants (Storek et al11 and J.S., unpublished observations, 2001). Of showed that baboons shedding bCMV from 1996 to 1998 still shed 158 infections with a known etiologic agent that occurred after the virus in 2002 (E. Blewett, unpublished observations, November engraftment (primarily caused by T-cell deficiency), 67 of 158 (42%) 2003, with permission), which is consistent with the lifetime viral infections were clearly caused by endogenous microorganisms (herpes- persistence documented for human CMV and EBV in infected viruses), and 34 of 158 (22%) infections were likely caused by humans.14 Collectively, bCMV and bLCV infections of baboons endogenous microorganisms (digestive tract bacteria and yeasts). Re- are useful models of clinically important persistent viral infections. lapse of the underlying hematologic malignancy occurred after transplan- To address whether CD4 T cells against persistent viruses tation in at least 15% of patients. can be generated de novo, we searched for YFP-marked CD4 T Human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) cells specific for bCMV or bLCV in bCMV/bLCV-seropositive are examples of viruses present in seropositive hosts during baboons that underwent transplantation with autologous YFP- posttransplantation immune reconstitution. They cause serious marked CD34 cells. From the Fred Hutchinson Cancer Research Center and the University of DK56465, and DK47754 from National Institutes of Health and by Research Washington School of Medicine, Seattle, WA; the 2nd Medical School, Charles Project No. 00000064203 from the Ministry of Health, Czech Republic. University, Prague, Czech Republic; the Oklahoma State University College of The online version of this article contains a data supplement. Osteopathic Medicine, Tulsa; and the University of Oklahoma Health Sciences Center, Oklahoma City. Reprints: Jan Storek, Department of Medicine, University of Calgary, 3330 Hospital Dr NW, HSC 1869, Calgary, Alberta, Canada T2N 4N1; e-mail: Submitted January 28, 2004; accepted September 5, 2004. Prepublished [email protected]. online as Blood First Edition Paper, October 12, 2004; DOI 10.1182/blood- 2004-01-0348. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby T.K. and H.L. contributed equally to this study. marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734. Supported by grants HL69710, AI46108, CA18221, HL53750, NCRR00166, © 2005 by The American Society of Hematology 2410 BLOOD, 15 MARCH 2005 ⅐ VOLUME 105, NUMBER 6 BLOOD, 15 MARCH 2005 ⅐ VOLUME 105, NUMBER 6 DE NOVO GENERATION OF T CELLS FOR HERPESVIRUSES 2411 effect, the cells were harvested and subjected to multiple freeze-thaw Materials and methods cycles. Then the cells were washed twice in glycine-buffered saline, and the pellets were sonicated on ice. After centrifugation at approximately 600g Animals and transplantation for 10 minutes, the virus-containing supernatants (from both bCMV strains) were mixed and heat inactivated at 56°C for 30 minutes. Protein concentra- Four juvenile baboons (Papio cynocephalus-anubis), seropositive for tion was determined with a BCA protein assay kit (Pierce, Rockford, IL). bCMV and bLCV before transplantation, underwent irradiation and trans- Aliquots of the bCMV lysate were stored in Ϫ80°C. Control lysate with the plantation with YFP marker gene–transduced autologous CD34 cells, as same protein concentration was prepared from uninfected MRC5 cells. decribed.23 Briefly, 100 ␮g/kg daily granulocyte–colony-stimulating factor LBLCs were obtained by outgrowth of bLCV-containing B cells from (G-CSF) and 50 ␮g/kg daily stem cell factor (SCF) were given subcutane- peripheral blood mononuclear cells in the presence of 1 ␮g/mL ously from day Ϫ8todayϪ4 to increase the number of CD34 cells in the cyclosporin A (animal M00093) or by infection of blood mononuclear marrow. On day Ϫ3, bone marrow was harvested into preservative-free cells with the supernatant of M00093-derived LBLCs (filtered through a heparin from both humeri and femora. CD34 cells were immunomagneti- 0.45-␮m filter) in the presence of 1 ␮g/mL cyclosporin A (animals cally enriched to 77% to 88% purity using antibody 12.8 and goat M00117, M00227, and J00116). anti–mouse immunoglobulin M (IgM)–coated microbeads (Miltenyi, Au- Peripheral blood mononuclear cells (MNCs), 1.5 ϫ 106, were incubated burn, CA) and were transduced according to the stem cell transduction in 1 mL RPMI 1640 supplemented with 2.05 mM glutamine, 25 mM protocol (described in the next section). After total body irradiation (10.2 HEPES (N-2-hydroxyethylpiperazine-NЈ-2-ethanesulfonic acid), 10% fetal Gy in 2 fractions at 0.07 Gy/min), the stem cells were reinfused on day 0. bovine serum (Hyclone, Logan, UT), anti-CD28 and anti-CD49d antibodies All animals were housed and cared for at the University of Washington (0.5 ␮g/mL each; BD Biosciences, San Jose, CA), recombinant baboon Regional Primate Research Center under conditions approved by the IL-7 (5 ng/mL; kindly provided by Dr Michel Morre, Cytheris, Vanves, American Association for the Accreditation of Laboratory Animal Care. France), and IL-15 (5 ng/mL; Peprotech, Rocky Hill, NJ) and were The study was approved by the University of Washington Animal Care and stimulated with bCMV lysate (5 ␮g protein/mL) or autologous LBLCs 5 Use Committee and the Fred Hutchinson Cancer Research Center (FH- (3 ϫ 10 ) overnight in a humidified incubator (5% CO2 and 37°C). Lysate CRC) Institutional Review Board. from uninfected MRC5 cells was used as the negative control for bCMV. For bLCV, no negative control was used during cell culture. However, Stem cell transduction protocol LBLCs without cultured MNCs were permeabilized and stained concur- rently to control for nonspecific antibody binding/fluorescence signal from Transduction of CD34 cells with yellow fluorescent protein (YFP) gene was LBLCs. To control for nonspecific stimulation of T cells by LBLCs during 24 performed as described. Briefly, the magnetically purified CD34 cells cell culture, MNCs from an EBV-seronegative animal were cultured with from the marrow of G-CSF– and SCF–primed baboons were cultured in autologous LBLCs. Brefeldin A (10 ␮g/mL; Sigma-Aldrich, St Louis, MO) Iscove medium with 10% fetal bovine serum and 100 ng/mL each of was added 2 hours after starting the culture. After overnight incubation, filgrastim (G-CSF), stem cell factor (SCF), megakaryocyte growth and cells were treated with 1 mM EDTA (ethylenediaminetetraacetic acid) for differentiation factor (MGDF), Flt3 ligand (Flt3L), IL-3, and IL-6 for 48 10 minutes at room temperature (RT). Then 2.5 mL FACS Lysing solution hours. All the cytokines were kindly donated by Dr Graham Molineux (BD Biosciences) was added for 10 minutes at RT.
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