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Science 300 (5617): 337-339

Copyright © 2003 by the American Association for the Advancement of Science

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}

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Dynamic Regulation of CD8 T Cell Tolerance Induction by Liver Sinusoidal Endothelial Cells.
A. Schurich, M. Berg, D. Stabenow, J. Bottcher, M. Kern, H. J. Schild, C. Kurts, V. Schuette, S. Burgdorf, L. Diehl, et al. (2010)
J. Immunol. 184, 4107-4114
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Dendritic cell targeted HIV gag protein vaccine provides help to a DNA vaccine including mobilization of protective CD8+ T cells.
G. Nchinda, D. Amadu, C. Trumpfheller, O. Mizenina, K. Uberla, and R. M. Steinman (2010)
PNAS 107, 4281-4286
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Mechanisms of control of acute Friend virus infection by CD4+ T helper cells and their functional impairment by regulatory T cells.
S. R. Nair, G. Zelinskyy, S. Schimmer, N. Gerlach, G. Kassiotis, and U. Dittmer (2010)
J. Gen. Virol. 91, 440-451
   Abstract »    Full Text »    PDF »
CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses.
J. J. Obar, M. J. Molloy, E. R. Jellison, T. A. Stoklasek, W. Zhang, E. J. Usherwood, and L. Lefrancois (2010)
PNAS 107, 193-198
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Early CD4+ T Cell Help Prevents Partial CD8+ T Cell Exhaustion and Promotes Maintenance of Herpes Simplex Virus 1 Latency.
G. M. Frank, A. J. Lepisto, M. L. Freeman, B. S. Sheridan, T. L. Cherpes, and R. L. Hendricks (2010)
J. Immunol. 184, 277-286
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Immunotherapy for Human Renal Cell Carcinoma by Adoptive Transfer of Autologous Transforming Growth Factor {beta}-Insensitive CD8+ T Cells.
L. Wang, W. Wen, J. Yuan, B. Helfand, Y. Li, C. Shi, F. Tian, J. Zheng, F. Wang, L. Chen, et al. (2010)
Clin. Cancer Res. 16, 164-173
   Abstract »    Full Text »    PDF »
HIV-1 Gag-specific immunity induced by a lentivector-based vaccine directed to dendritic cells.
B. Dai, L. Yang, H. Yang, B. Hu, D. Baltimore, and P. Wang (2009)
PNAS 106, 20382-20387
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Activation-Induced CD154 Expression Abrogates Tolerance Induced by Apoptotic Cells.
P. Gurung, T. A. Kucaba, T. A. Ferguson, and T. S. Griffith (2009)
J. Immunol. 183, 6114-6123
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Partial CD4 Depletion Reduces Regulatory T Cells Induced by Multiple Vaccinations and Restores Therapeutic Efficacy.
M. G. LaCelle, S. M. Jensen, and B. A. Fox (2009)
Clin. Cancer Res. 15, 6881-6890
   Abstract »    Full Text »    PDF »
Myeloma cell line-derived, pooled heat shock proteins as a universal vaccine for immunotherapy of multiple myeloma.
J. Qian, S. Hong, S. Wang, L. Zhang, L. Sun, M. Wang, J. Yang, L. W. Kwak, J. Hou, and Q. Yi (2009)
Blood 114, 3880-3889
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Identification of 4 new HLA-DR-restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity.
A. N. Stumpf, E. D. van der Meijden, C. A. M. van Bergen, R. Willemze, J. H. F. Falkenburg, and M. Griffioen (2009)
Blood 114, 3684-3692
   Abstract »    Full Text »    PDF »
EBV-Induced Human CD8+ NKT Cells Suppress Tumorigenesis by EBV-Associated Malignancies.
H. Yuling, X. Ruijing, L. Li, J. Xiang, Z. Rui, W. Yujuan, Z. Lijun, D. Chunxian, T. Xinti, X. Wei, et al. (2009)
Cancer Res. 69, 7935-7944
   Abstract »    Full Text »    PDF »
The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection.
S. Asabe, S. F. Wieland, P. K. Chattopadhyay, M. Roederer, R. E. Engle, R. H. Purcell, and F. V. Chisari (2009)
J. Virol. 83, 9652-9662
   Abstract »    Full Text »    PDF »
Highly Efficient Antiviral CD8+ T-Cell Induction by Peptides Coupled to the Surfaces of Liposomes.
A. Takagi, M. Matsui, S. Ohno, H. Duan, O. Moriya, N. Kobayashi, H. Oda, M. Mori, A. Kobayashi, M. Taneichi, et al. (2009)
Clin. Vaccine Immunol. 16, 1383-1392
   Abstract »    Full Text »    PDF »
Impact of Cytotoxic-T-Lymphocyte Memory Induction without Virus-Specific CD4+ T-Cell Help on Control of a Simian Immunodeficiency Virus Challenge in Rhesus Macaques.
T. Tsukamoto, A. Takeda, T. Yamamoto, H. Yamamoto, M. Kawada, and T. Matano (2009)
J. Virol. 83, 9339-9346
   Abstract »    Full Text »    PDF »
CD4+ T Cell Help Has an Epitope-Dependent Impact on CD8+ T Cell Memory Inflation during Murine Cytomegalovirus Infection.
C. M. Snyder, A. Loewendorf, E. L. Bonnett, M. Croft, C. A. Benedict, and A. B. Hill (2009)
J. Immunol. 183, 3932-3941
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Kinetics and Phenotype of Vaccine-Induced CD8+ T-Cell Responses to Toxoplasma gondii.
K. A. Jordan, E. H. Wilson, E. D. Tait, B. A. Fox, D. S. Roos, D. J. Bzik, F. Dzierszinski, and C. A. Hunter (2009)
Infect. Immun. 77, 3894-3901
   Abstract »    Full Text »    PDF »
Human Immunodeficiency Virus Type 1 Escapes from Interleukin-2-Producing CD4+ T-Cell Responses without High-Frequency Fixation of Mutations.
R. B. Jones, F.-Y. Yue, X. X. J. Gu, D. V. Hunter, S. Mujib, G. Gyenes, R. D. Mason, R. Mohamed, K. S. MacDonald, C. Kovacs, et al. (2009)
J. Virol. 83, 8722-8732
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Strong Ability of Nef-Specific CD4+ Cytotoxic T Cells To Suppress Human Immunodeficiency Virus Type 1 (HIV-1) Replication in HIV-1-Infected CD4+ T Cells and Macrophages.
N. Zheng, M. Fujiwara, T. Ueno, S. Oka, and M. Takiguchi (2009)
J. Virol. 83, 7668-7677
   Abstract »    Full Text »    PDF »
Immunity to Murine Prostatic Tumors: Continuous Provision of T-Cell Help Prevents CD8 T-Cell Tolerance and Activates Tumor-Infiltrating Dendritic Cells.
K. A. Shafer-Weaver, S. K. Watkins, M. J. Anderson, L. J. Draper, A. Malyguine, W. G. Alvord, N. M. Greenberg, and A. A. Hurwitz (2009)
Cancer Res. 69, 6256-6264
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Functional Unresponsiveness and Replicative Senescence of Myeloid Leukemia Antigen-specific CD8+ T Cells After Allogeneic Stem Cell Transplantation.
G. L. Beatty, J. S. Smith, R. Reshef, K. P. Patel, T. A. Colligon, B. A. Vance, N. V. Frey, F. B. Johnson, D. L. Porter, and R. H. Vonderheide (2009)
Clin. Cancer Res. 15, 4944-4953
   Abstract »    Full Text »    PDF »

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