CTLA-4 dysregulation of self/tumor-reactive CD8⁺ T-cell function is CD4⁺ T-cell dependent

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 glycoprotein (gp) 100-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 on the absence of CTLA-4 on CD8⁺ T cells. These results indicated that CD8⁺ CLTA-4^-/- T-cell-mediated autoimmunity and tumor immunity required CD4⁺ T cells in which the function was dysregulated by the absence of CTLA-4-mediated negative costimulation.