Lack of coreceptor allows survival of chronically stimulated double-negative alpha/beta T cells: Implications for autoimmunity

Lymphoproliferative diseases arts characterized by massive accumulation of CD4(-)CD8(-)B220(+) (double-negative [DN]) T cells in peripheral organs. Al though evidence indicates these cells are derived from mature autoreactive alpha/beta 7 cells, the significance of coreceptor downregulation is trot k nown. In this study, we examined the role CD4 coreceptor plays in the survi val of repeatedly stimulated T cells. CD4(+/+) and CD4(-/-) 7 cells from AN D T cell receptor (TCR) transgenic mice exhibited similar phenotypes after antigenic stimulation, but the CD4(-/-) T cells survived in much larger num bers than the CD4(+/+) cells upon primary and secondary major histocompatib ility complex (MHC)/peptide stimulation. Enhanced survival of CD4(-/-) 7 ce lls was due to decreased apoptosis rather than enhanced proliferation. Simi larly, circumvention of the CD4/MHC interaction by using a surrogate TCR li gand that does not engage CD4 led to significant enhancement of CD4(+/+) ce lls than when stimulated with MHC/peptide. Finally, we generated DN B220(+) 7 cells using an in vitro model system and showed they were more tolerant to chronic stimulation than CD4(+/+) cells. Together, these results indicat e that coreceptor engagement controls expansion of normal 7 cells. In the a bsence of coreceptor, T cells survive chronic stimulation and express B220 as seen in autoimmune lymphoproliferative diseases.