Model of cDC2 cross-presentation regulated by MHC-II deficiency. T cell activation requires engagement of both T cell receptors (TCR) and receptors for costimulatory molecules (e.g., CD28) by, respectively, MHC-peptide complex (p-MHC-I for CD8 T and p-MHC-II for CD4 T and Treg) and costimulatory molecules on DC (e.g., CD80). In WT mice, CD8 T cells (that mediate tumor killing) are typically primed by cDC1 and CD4 T cells (including Treg) are primed by cDC2; the outcome is that WT hosts are usually tolerant to syngeneic tumors and the tumors expand (left). In contrast, reducing or deleting MHC-II expression or function on cDC2 results in the expansion of the cDC2 population, their elevated MHC-I expression, and enhanced cDC2 cross-priming activity, all of which favor CD8 T proliferation. Conversely, the activation and proliferation of Treg are impeded due to the absence of Treg–cDC2 interaction mediated by TCR and p-MHC-II. The net result is tumor growth inhibition (right). MHC-II deficiency could be achieved by monoclonal antibody HB12-18 treatment or CIITA inhibition.