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Original Article

Lack of Coreceptor Allows Survival of Chronically Stimulated Double-Negative /β T Cells

Abdel Rahim A. Hamad^a, Ananth Srikrishnan^a, Paria Mirmonsef^a, Chris P.M. Broeren^c, Carl H. June^d, Drew Pardoll^b, and Jonathan P. Schneck^a

^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
Dept. of Pathology, Johns Hopkins School of Medicine, 720 Rutland Ave., Ross 664G, Baltimore, MD 21211.410-614-3548410-614-0642

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 /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.

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

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.

© 2001 The Rockefeller University Press

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