Divergent Roles for CD4+ T Cells in the Priming and Effector/Memory Phases of Adoptive Immunotherapy

Abstract

The requirement for CD4+ Th cells in the cross-priming of antitumor CTL is well accepted in tumor immunology. Here we report that the requirement for T cell help can be replaced by local production of GM-CSF at the vaccine site. Experiments using mice in which CD4+ T cells were eliminated, either by Ab depletion or by gene knockout of the MHC class II β-chain (MHC II KO), revealed that priming of therapeutic CD8+ effector T cells following vaccination with a GM-CSF-transduced B16BL6-D5 tumor cell line occurred independently of CD4+ T cell help. The adoptive transfer of CD8+ effector T cells, but not CD4+ effector T cells, led to complete regression of pulmonary metastases. Regression of pulmonary metastases did not require either host T cells or NK cells. Transfer of CD8+ effector T cells alone could cure wild-type animals of systemic tumor; the majority of tumor-bearing mice survived long term after treatment (>100 days). In contrast, adoptive transfer of CD8+ T cells to tumor-bearing MHC II KO mice improved survival, but eventually all MHC II KO mice succumbed to metastatic disease. WT mice cured by adoptive transfer of CD8+ T cells were resistant to tumor challenge. Resistance was mediated by CD8+ T cells in mice at 50 days, while both CD4+ and CD8+ T cells were important for protection in mice challenged 150 days following adoptive transfer. Thus, in this tumor model CD4+ Th cells are not required for the priming phase of CD8+ effector T cells; however, they are critical for both the complete elimination of tumor and the maintenance of a long term protective antitumor memory response in vivo.