(A) Mouse hosts with human TCR and HLA genes generate “optimal-affinity” TCRs. As opposed to human hosts — which display self-antigens in the thymus and delete T cells that bind self-MHC and self-peptide with high affinity in a process known as negative selection — mouse hosts that lack human peptides but have human TCRs and HLA molecules can generate TCRs that bind human MHC and human peptide with high affinity. These are so-called optimal-affinity TCRs. (B) The wide range of effector and helper roles of CD4⁺ T cells in the antitumor response. CD4⁺ T cells can directly lyse tumor cells that have constitutive or inducible MHC II expression. Additionally, they can indirectly lead to tumor cell lysis by recruiting and activating macrophages and NK cells, which can release tumor antigens that can be presented by professional antigen-presenting cells such as dendritic cells to CD8⁺ T cells. Finally, they can also license dendritic cells, enhancing the activation and memory formation of tumor-specific CD8⁺ T cells.