Macrophage activation: A new insight

The inflammatory response is indispensable for protective immunity, yet virulent pathogens, whether bacteria or viruses, often elicit greatly excessive inflammation, ‘cytokine storm’, harmful to the host. Full T-cell activation requires interaction of costimulatory receptors B7-1 (CD80) and B7-2 (CD86), expressed on antigen-presenting cells (APC), with CD28 expressed on the T cell. It is currently thought that the B7/CD28 costimulatory axis signals solely in one direction, from the APC into the T cell. We focus on a brand-new basic concept: retrosignaling through the B7/CD28 axis, backwards into the APC, controls Toll-like receptor (TLR)-mediated inflammatory cytokine responses of APC. Our finding is that induction by a broad set of TLR agonists of APC-specific cytokines such as IL-1β and IL-1α depends on the presence of T cells. We could show that cytokine expression mediated by TLR agonists in APC is abolished completely when depleting human PBMC from CD3-positive T cells. However, whether T cells signal back into the APC in a direct manner through the B7/CD28 axis, or whether they signal indirectly through cytokines from T cells remains a central question. In addition, if signaling by T cells to APC is indirect, which cytokines are involved? For TLR2/6 inducer Zymosan we could show that IL-1α and IL-1β expression is dependent on inflammatory cytokine IFN-γ, expressed specifically by T cells. Hence, induction through TLR2/6, signaling is indirect and not direct through the B7/CD28 costimulatory axis and depends on IFN-γ.