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Science 11 April 2003:
Vol. 300. no. 5617, pp. 337 - 339
DOI: 10.1126/science.1082305
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Reports

Requirement for CD4 T Cell Help in Generating Functional CD8 T Cell Memory

Devon J. Shedlock, Hao Shen*

Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.

Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
*   To whom correspondence should be addressed at the Department of Microbiology, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104-6076, USA. E-mail: hshen{at}mail.med.upenn.edu

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Infect. Immun. 75, 5956-5966
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Defects in the Acquisition of CD8 T Cell Effector Function after Priming with Tumor or Soluble Antigen Can Be Overcome by the Addition of an OX40 Agonist.
W. L. Redmond, M. J. Gough, B. Charbonneau, T. L. Ratliff, and A. D. Weinberg (2007)
J. Immunol. 179, 7244-7253
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Vaccines Based on Novel Adeno-Associated Virus Vectors Elicit Aberrant CD8+ T-Cell Responses in Mice.
J. Lin, Y. Zhi, L. Mays, and J. M. Wilson (2007)
J. Virol. 81, 11840-11849
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Human Immunodeficiency Virus Type 1 Controllers but Not Noncontrollers Maintain CD4 T Cells Coexpressing Three Cytokines.
S. Kannanganat, B. G. Kapogiannis, C. Ibegbu, L. Chennareddi, P. Goepfert, H. L. Robinson, J. Lennox, and R. R. Amara (2007)
J. Virol. 81, 12071-12076
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Increasing the Survival of Dendritic Cells In Vivo Does Not Replace the Requirement for CD4+ T Cell Help during Primary CD8+ T Cell Responses.
K. E. Matthews, J. S. Qin, J. Yang, I. F. Hermans, M. J. Palmowski, V. Cerundolo, and F. Ronchese (2007)
J. Immunol. 179, 5738-5747
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Cognate Memory CD4+ T Cells Generated with Dendritic Cell Priming Influence the Expansion, Trafficking, and Differentiation of Secondary CD8+ T Cells and Enhance Tumor Control.
M. L. Hwang, J. R. Lukens, and T. N. J. Bullock (2007)
J. Immunol. 179, 5829-5838
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The Surprising Kinetics of the T Cell Response to Live Antigenic Cells.
A. J. Tyznik and M. J. Bevan (2007)
J. Immunol. 179, 4988-4995
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Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help.
Y. Zhai, Y. Wang, Z. Wu, and J. W. Kupiec-Weglinski (2007)
J. Immunol. 179, 4529-4534
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CD8+ T Cell Protective Immunity against Chlamydia pneumoniae Includes an H2-M3-Restricted Response That Is Largely CD4+ T Cell-Independent.
A. Tvinnereim and B. Wizel (2007)
J. Immunol. 179, 3947-3957
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Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells.
A. M. Intlekofer, N. Takemoto, C. Kao, A. Banerjee, F. Schambach, J. K. Northrop, H. Shen, E. J. Wherry, and S. L. Reiner (2007)
J. Exp. Med. 204, 2015-2021
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Role of Human Immunodeficiency Virus (HIV)-Specific T-Cell Immunity in Control of Dual HIV-1 and HIV-2 Infection.
N. N. Zheng, M. J. McElrath, P.-S. Sow, S. E. Hawes, H. Diallo-Agne, J. E. Stern, F. Li, A. L. Mesher, A. D. Robinson, G. S. Gottlieb, et al. (2007)
J. Virol. 81, 9061-9071
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CD8+ T Cell-Mediated Airway Hyperresponsiveness and Inflammation Is Dependent on CD4+IL-4+ T Cells.
T. Koya, N. Miyahara, K. Takeda, S. Matsubara, H. Matsuda, C. Swasey, A. Balhorn, A. Dakhama, and E. W. Gelfand (2007)
J. Immunol. 179, 2787-2796
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Tumors Hamper the Immunogenic Competence of CD4+ T Cell-Directed Dendritic Cell Vaccination.
V. S. Zimmermann, A. Casati, C. Schiering, S. Caserta, R. Hess Michelini, V. Basso, and A. Mondino (2007)
J. Immunol. 179, 2899-2909
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Immunologic evidence for lack of heterologous protection following resolution of HCV in patients with non genotype 1 infection.
J. Schulze zur Wiesch, G. M. Lauer, J. Timm, T. Kuntzen, M. Neukamm, A. Berical, A. M. Jones, B. E. Nolan, S. A. Longworth, V. Kasprowicz, et al. (2007)
Blood 110, 1559-1569
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Mouse Dendritic-Endothelial Cell Hybrids and 4-1BB Costimulation Elicit Antitumor Effects Mediated by Broad Antiangiogenic Immunity.
E. Ko, W. Luo, L. Peng, X. Wang, and S. Ferrone (2007)
Cancer Res. 67, 7875-7884
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Multiple-Cytokine-Producing Antiviral CD4 T Cells Are Functionally Superior to Single-Cytokine-Producing Cells.
S. Kannanganat, C. Ibegbu, L. Chennareddi, H. L. Robinson, and R. R. Amara (2007)
J. Virol. 81, 8468-8476
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OX40 Costimulation Promotes Persistence of Cytomegalovirus-Specific CD8 T Cells: A CD4-Dependent Mechanism.
I. R. Humphreys, A. Loewendorf, C. de Trez, K. Schneider, C. A. Benedict, M. W. Munks, C. F. Ware, and M. Croft (2007)
J. Immunol. 179, 2195-2202
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Memory CD4+ T-Lymphocyte Loss and Dysfunction during Primary Simian Immunodeficiency Virus Infection.
Y. Sun, S. R. Permar, A. P. Buzby, and N. L. Letvin (2007)
J. Virol. 81, 8009-8015
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Induction of CD4-Independent E7-Specific CD8+ Memory Response by Heat Shock Fusion Protein.
H. Liu, B. H. Wu, G. J. Rowse, and P. C. R. Emtage (2007)
Clin. Vaccine Immunol. 14, 1013-1023
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The Antiviral CD8+ T Cell Response Is Differentially Dependent on CD4+ T Cell Help Over the Course of Persistent Infection.
C. C. Kemball, C. D. Pack, H. M. Guay, Z.-N. Li, D. A. Steinhauer, E. Szomolanyi-Tsuda, and A. E. Lukacher (2007)
J. Immunol. 179, 1113-1121
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Protection from Lethal Infection by Adoptive Transfer of CD8 T Cells Genetically Engineered to Express Virus-Specific Innate Immune Receptor.
K. Iizuka, C. Nakajima, Y.-M. Iizuka, M. Takase, T. Kato, S. Noda, K. Tanaka, and O. Kanagawa (2007)
J. Immunol. 179, 1122-1128
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Memory CD4 T Cells Enhance Primary CD8 T-Cell Responses.
C. M. Krawczyk, H. Shen, and E. J. Pearce (2007)
Infect. Immun. 75, 3556-3560
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Induction of Postsurgical Tumor Immunity and T-Cell Memory by a Poorly Immunogenic Tumor.
P. Zhang, A. L. Cote, V. C. de Vries, E. J. Usherwood, and M. J. Turk (2007)
Cancer Res. 67, 6468-6476
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