Lymphoproliferative diseases are characterized by massive accumulation of CD4−CD8−B220+ (double-negative [DN]) T cells in peripheral organs. Although evidence indicates these cells are derived from mature autoreactive α/β T cells, the significance of coreceptor downregulation is not known. In this study, we examined the role CD4 coreceptor plays in the survival of repeatedly stimulated T cells. CD4+/+ and CD4−/− T cells from AND T cell receptor (TCR) transgenic mice exhibited similar phenotypes after antigenic stimulation, but the CD4−/− T cells survived in much larger numbers than the CD4+/+ cells upon primary and secondary major histocompatibility complex (MHC)/peptide stimulation. Enhanced survival of CD4−/− T cells was due to decreased apoptosis rather than enhanced proliferation. Similarly, circumvention of the CD4/MHC interaction by using a surrogate TCR ligand that does not engage CD4 led to significant enhancement of CD4+/+ cells than when stimulated with MHC/peptide. Finally, we generated DN B220+ T cells using an in vitro model system and showed they were more tolerant to chronic stimulation than CD4+/+ cells. Together, these results indicate that coreceptor engagement controls expansion of normal T cells. In the absence of coreceptor, T cells survive chronic stimulation and express B220 as seen in autoimmune lymphoproliferative diseases.
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21 May 2001
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May 14 2001
Lack of Coreceptor Allows Survival of Chronically Stimulated Double-Negative α/β T Cells: Implications for Autoimmunity
Abdel Rahim A. Hamad,
Abdel Rahim A. Hamad
aDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Ananth Srikrishnan,
Ananth Srikrishnan
aDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Paria Mirmonsef,
Paria Mirmonsef
aDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Chris P.M. Broeren,
Chris P.M. Broeren
cDepartment of Immunology, Institute of Infectious Diseases and Immunology, University of Utrecht, 3584 CL Utrecht, The Netherlands
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Carl H. June,
Carl H. June
dStellar Chance Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Drew Pardoll,
Drew Pardoll
bDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Jonathan P. Schneck
Jonathan P. Schneck
aDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Abdel Rahim A. Hamad
aDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Ananth Srikrishnan
aDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Paria Mirmonsef
aDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Chris P.M. Broeren
cDepartment of Immunology, Institute of Infectious Diseases and Immunology, University of Utrecht, 3584 CL Utrecht, The Netherlands
Carl H. June
dStellar Chance Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Drew Pardoll
bDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Jonathan P. Schneck
aDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
C.H. June's present address is Abrameson Family Cancer Research Institute and Dept. of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA 19104.
Abbreviations used in this paper: AICD, activation-induced cell death; CFSE, 5- and 6-carboxyfluorescein diacetate succinimidyl ester; DN, double-negative; MCC, moth cytochrome c; tg, transgenic.
Received:
October 13 2000
Revision Requested:
February 21 2001
Accepted:
April 09 2001
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2001 The Rockefeller University Press
2001
The Rockefeller University Press
J Exp Med (2001) 193 (10): 1113–1122.
Article history
Received:
October 13 2000
Revision Requested:
February 21 2001
Accepted:
April 09 2001
Citation
Abdel Rahim A. Hamad, Ananth Srikrishnan, Paria Mirmonsef, Chris P.M. Broeren, Carl H. June, Drew Pardoll, Jonathan P. Schneck; Lack of Coreceptor Allows Survival of Chronically Stimulated Double-Negative α/β T Cells: Implications for Autoimmunity. J Exp Med 21 May 2001; 193 (10): 1113–1122. doi: https://doi.org/10.1084/jem.193.10.1113
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