CD4 and CD8: an inside-out coreceptor model for innate immune cells

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 Fc gamma R-dependent responses of human monocytes. Building on data that key components of TCR and Fc gamma R signaling can substitute one another efficiently, we postulate that CD4 and CD8 operate with Fc gamma R 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 Fc gamma R 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. J. Leukoc. Biol. 86: 251-259; 2009.