Lack of Coreceptor Allows Survival of Chronically Stimulated Double-Negative α/β T Cells: Implications for Autoimmunity

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.