The Journal of Experimental Medicine
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Published online 14 May 2001.
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© The Rockefeller University Press, 0022-1007/2001/5/1113/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 10, May 21, 2001 1113-1122

Original Article

Lack of Coreceptor Allows Survival of Chronically Stimulated Double-negative {alpha}/ß T Cells: Implications for Autoimmunity

Abdel Rahim A. Hamada, Ananth Srikrishnana, Paria Mirmonsefa, Chris P.M. Broerenc, Carl H. Juned, Drew Pardollb, and Jonathan P. Schnecka
a Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
b Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
c Department of Immunology, Institute of Infectious Diseases and Immunology, University of Utrecht, 3584 CL Utrecht, The Netherlands
d Stellar Chance Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence to: Abdel Rahim A. Hamad, Dept. of Pathology, Johns Hopkins School of Medicine, 720 Rutland Ave., Ross 664G, Baltimore, MD 21211. Tel:410-614-0642 Fax:410-614-3548 E-mail:ahamad{at}jhmi.edu.

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 {alpha}/ß 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.

Key Words: CD4 coreceptor, double-negative T cell, lymphoproliferation, B220, apoptosis


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