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*
Vaccine and Gene Therapy Institute, Oregon Regional Primate Research Center, Oregon Health and Science University, West Campus, Beaverton, OR 97006; and
BD Biosciences, San Jose, CA 95131
The rhesus macaque (RM) is a critical animal model for studies of
viral pathogenesis and immunity, yet fundamental aspects of their
cellular immune response remain poorly defined. One such deficiency is
the lack of validated phenotypic signatures for their naive and memory
T cell subsets, and the resultant unavailability of accurate
information on their memory T cell development, homeostasis, and
function. In this study, we report a phenotypic paradigm allowing
definitive characterization of these subsets and their comprehensive
functional analysis. Naive T cells are optimally delineated by their
homogeneous CD95lowCD28high
7
integrinint (CD4+) or
CD95lowCD28intCD11alow
(CD8+) phenotypes. This subset 1) was present in blood and
secondary lymph tissues, but not effector sites; 2) vastly predominated
in the fetal/neonatal immune system, but rapidly diminished with
postnatal age; 3) lacked IFN-
production capability, and specific
responses to RM CMV; and 4) demonstrated low in vivo proliferative
activity. CD4+ and CD8+ memory subsets were
CD95high, but otherwise phenotypically heterogeneous and
included all IFN- production, RM CMV-specific responses, effector
site T cells, and demonstrated high in vivo proliferative activity
(
10 times the naive subset). These analyses also revealed the RM
"effector memory" subset within the overall memory population. This
population, best defined by lack of CD28 expression, contained the
majority of RM CMV-specific cells, was highly enriched in extralymphoid
effector sites, and comprised an increasing proportion of total memory
cells with age. The effector memory subset demonstrated similar in vivo
proliferative activity and survival as CD28+ "central
memory" T cells, consistent with independent homeostatic
regulation.
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C. K. Asiedu, K. J. Goodwin, G. Balgansuren, S. M. Jenkins, S. Le Bas-Bernardet, U. Jargal, D. M. Neville Jr, and J. M. Thomas Elevated T Regulatory Cells in Long-Term Stable Transplant Tolerance in Rhesus Macaques Induced by Anti-CD3 Immunotoxin and Deoxyspergualin J. Immunol., December 15, 2005; 175(12): 8060 - 8068. [Abstract] [Full Text] [PDF]
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U. Wille-Reece, B. J. Flynn, K. Lore, R. A. Koup, R. M. Kedl, J. J. Mattapallil, W. R. Weiss, M. Roederer, and R. A. Seder HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates PNAS, October 18, 2005; 102(42): 15190 - 15194. [Abstract] [Full Text] [PDF]
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Y. Sun, J. E. Schmitz, P. M. Acierno, S. Santra, R. A. Subbramanian, D. H. Barouch, D. A. Gorgone, M. A. Lifton, K. R. Beaudry, K. Manson, et al. Dysfunction of Simian Immunodeficiency Virus/Simian Human Immunodeficiency Virus-Induced IL-2 Expression by Central Memory CD4+ T Lymphocytes J. Immunol., April 15, 2005; 174(8): 4753 - 4760. [Abstract] [Full Text] [PDF]
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G. Silvestri, A. Fedanov, S. Germon, N. Kozyr, W. J. Kaiser, D. A. Garber, H. McClure, M. B. Feinberg, and S. I. Staprans Divergent Host Responses during Primary Simian Immunodeficiency Virus SIVsm Infection of Natural Sooty Mangabey and Nonnatural Rhesus Macaque Hosts J. Virol., April 1, 2005; 79(7): 4043 - 4054. [Abstract] [Full Text] [PDF]
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 G. Ramesh, X. Alvarez, J. T. Borda, P. P. Aye, A. A. Lackner, and K. Sestak Visualizing Cytokine-Secreting Cells In Situ in the Rhesus Macaque Model of Chronic Gut Inflammation Clin. Vaccine Immunol., January 1, 2005; 12(1): 192 - 197. [Abstract] [Full Text] [PDF]
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 M. Conklyn, C. Andresen, P. Changelian, and E. Kudlacz The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing J. Leukoc. Biol., December 1, 2004; 76(6): 1248 - 1255. [Abstract] [Full Text] [PDF]
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L. J. Picker, S. I. Hagen, R. Lum, E. F. Reed-Inderbitzin, L. M. Daly, A. W. Sylwester, J. M. Walker, D. C. Siess, M. Piatak Jr., C. Wang, et al. Insufficient Production and Tissue Delivery of CD4+ Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection J. Exp. Med., November 15, 2004; 200(10): 1299 - 1314. [Abstract] [Full Text] [PDF]
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K. Sestak, M. M. McNeal, A. Choi, M. J. Cole, G. Ramesh, X. Alvarez, P. P. Aye, R. P. Bohm, M. Mohamadzadeh, and R. L. Ward Defining T-Cell-Mediated Immune Responses in Rotavirus-Infected Juvenile Rhesus Macaques J. Virol., October 1, 2004; 78(19): 10258 - 10264. [Abstract] [Full Text] [PDF]
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M. Moniuszko, T. Fry, W.-P. Tsai, M. Morre, B. Assouline, P. Cortez, M. G. Lewis, S. Cairns, C. Mackall, and G. Franchini Recombinant Interleukin-7 Induces Proliferation of Naive Macaque CD4+ and CD8+ T Cells In Vivo J. Virol., September 15, 2004; 78(18): 9740 - 9749. [Abstract] [Full Text] [PDF]
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Y. Nishimura, T. Igarashi, O. K. Donau, A. Buckler-White, C. Buckler, B. A. P. Lafont, R. M. Goeken, S. Goldstein, V. M. Hirsch, and M. A. Martin Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses PNAS, August 17, 2004; 101(33): 12324 - 12329. [Abstract] [Full Text] [PDF]
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K. Abel, L. La Franco-Scheuch, T. Rourke, Z.-M. Ma, V. de Silva, B. Fallert, L. Beckett, T. A. Reinhart, and C. J. Miller Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques J. Virol., January 15, 2004; 78(2): 841 - 854. [Abstract] [Full Text] [PDF]
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Y. Yue, S. S. Zhou, and P. A. Barry Antibody responses to rhesus cytomegalovirus glycoprotein B in naturally infected rhesus macaques J. Gen. Virol., December 1, 2003; 84(12): 3371 - 3379. [Abstract] [Full Text] [PDF]
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B. Gansuvd, W. J. Hubbard, A. Hutchings, F. T. Thomas, J. Goodwin, S. B. Wilson, M. A. Exley, and J. M. Thomas Phenotypic and Functional Characterization of Long-Term Cultured Rhesus Macaque Spleen-Derived NKT Cells J. Immunol., September 15, 2003; 171(6): 2904 - 2911. [Abstract] [Full Text] [PDF]
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M. C. Strain, H. F. Gunthard, D. V. Havlir, C. C. Ignacio, D. M. Smith, A. J. Leigh-Brown, T. R. Macaranas, R. Y. Lam, O. A. Daly, M. Fischer, et al. Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: Intrinsic stability predicts lifelong persistence PNAS, April 15, 2003; 100(8): 4819 - 4824. [Abstract] [Full Text] [PDF]
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C. Sugimoto, K. Tadakuma, I. Otani, T. Moritoyo, H. Akari, F. Ono, Y. Yoshikawa, T. Sata, S. Izumo, and K. Mori nef Gene Is Required for Robust Productive Infection by Simian Immunodeficiency Virus of T-Cell-Rich Paracortex in Lymph Nodes J. Virol., April 1, 2003; 77(7): 4169 - 4180. [Abstract] [Full Text] [PDF]
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T. J. Fry, M. Moniuszko, S. Creekmore, S. J. Donohue, D. C. Douek, S. Giardina, T. T. Hecht, B. J. Hill, K. Komschlies, J. Tomaszewski, et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates Blood, March 15, 2003; 101(6): 2294 - 2299. [Abstract] [Full Text] [PDF]
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E. V. Ravkov, C. M. Myrick, and J. D. Altman Immediate Early Effector Functions of Virus-Specific CD8+CCR7+ Memory Cells in Humans Defined by HLA and CC Chemokine Ligand 19 Tetramers J. Immunol., March 1, 2003; 170(5): 2461 - 2468. [Abstract] [Full Text] [PDF]
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