IFN-gamma-dependent inhibition of tumor angiogenesis by tumor-infiltrating CD4+ T cells requires tumor responsiveness to IFN-gamma.

The importance of CD4(+) T cells in the induction of an optimal antitumor immune response has largely been attributed to their ability to provide costimulatory signals for the priming of MHC class I-restricted CD8(+) CTL. However, many reports have demonstrated a requirement for CD4(+) T cells in the effector phase of tumor rejection indicating a greater responsibility for CD4(+) T cells in controlling tumor outgrowth. We demonstrate here a critical role for CD4(+) T cells in restraining initial tumor development through the inhibition of tumor angiogenesis. Using a tumor variant that is unresponsive to IFN-gamma, we show that tumor responsiveness to IFN-gamma is necessary for IFN-gamma-dependent inhibition of tumor angiogenesis by CD4(+) T cells. These studies reveal a pivotal role for CD4(+) T cells in controlling early tumor development through inhibition of tumor angiogenesis.