CD8 and CD4 are expressed by several cell types that do not express TCR. These include DCs, macrophages, monocytes, and NK cells. CD8(+) monocytes and macrophages are abundant at the site of pathology in many rat disease models, particularly those involving immune complex-mediated pathology. Indeed, in some disease models, CD8(+) macrophages correlate with severity of pathology or directly cause pathology or tumor cell killing. Evidence suggests CD8 or CD4 can enhance FcgammaR-dependent responses of human monocytes. Building on data that key components of TCR and FcgammaR signaling can substitute one another efficiently, we postulate that CD4 and CD8 operate with FcgammaR and potentially other receptors to enhance responses of T cells and various innate immune cells. Our model suggests CD8 on myeloid cells may contribute directly to tumor killing and tissue pathology by enhancing FcgammaR responses. Moreover, the model suggests a role for CD8 in cross-presentation of antibody-associated antigen by DCs and a new mechanism to regulate TCR sensitivity.