Submitted November 3, 2005
Accepted July 20, 2006
CTLA-4 dysregulation of self/tumor-reactive CD8+ T cell function is CD4+ T cell-dependent
Luca Gattinoni, Anju Ranganathan, Deborah R Surman, Douglas C Palmer, Paul A Antony, Marc R Theoret, David M Heimann, Steven A Rosenberg, and Nicholas P Restifo*
National Cancer Institute, NIH, Bethesda, MD, USA
National Cancer Institute and Howard Hughes Medical Institute-National Institutes of Health Research
National Cancer Institute and Howard Hughes Medical Institute-National
* Corresponding author; email: restifo{at}nih.gov.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)
maintains peripheral tolerance by suppressing T cell
activation and proliferation but its precise role in
vivo remains unclear. We sought to elucidate the impact
of CTLA-4 expression on self/tumor-reactive CD8+ T cells
by using the gp100-specific T-cell receptor (TCR)
transgenic mouse, pmel-1. Pmel-1 CLTA-4-/- mice
developed profound, accelerated autoimmune vitiligo.
This enhanced autoimmunity was associated with a small
but highly activated CD8+ T cell population and large
numbers of CD4+ T cells not expressing the transgenic
TCR. Adoptive transfer of pmel-1 CLTA-4-/-CD8+ T cells
did not mediate superior antitumor immunity in the
settings of either large established tumors or tumor
challenge, suggesting that the mere absence of CTLA-4-
mediated inhibition on CD8+ T cells did not directly
promote enhancement of their effector functions. Removal
of CD4+ T cells by crossing the pmel-1 CLTA-4-/- mouse
onto a Rag-1-/- background resulted in the complete
abrogation of CD8+ T cell activation and autoimmune
manifestations. The effects of CD4+ CLTA-4-/- T cells
were dependent of the absence of CTLA-4 on CD8+ T cells.
These results indicated that CD8+ CLTA-4-/- T cell-
mediated auto- and tumor-immunity required CD4+ T cells
whose function was dysregulated by the absence of CTLA-4-
mediated negative costimulation.
