The power of combinatorial immunology: IL-12 and IL-12-related dimeric cytokines in infectious diseases

Appropriate induction of a Th1 immune response is required for effective antimicrobial immunity. However, dysregulated Th1 immune responses after infection may also lead to immunopathology. Thus, cell-mediated immune responses have to be tightly regulated. Upon infection, the production of interleukin (IL)-12, a heterodimeric cytokine composed of a p35 and a p40 subunit, is the dominant factor in Th1 cell development. The recent discovery of novel dimeric cytokines closely related to IL-12 add now to our understanding of cellular immunity and the fine tuning of T cell responses. At the onset of infection, IL-27, a heterodimer composed of the IL-12p40-related protein EBI-3 (Epstein-Barr virus-induced gene 3) and the IL-12p35-related protein p28 induces the expression of a functional IL-12 receptor in naive CD4+ T cells, making these cells sensitive to IL-12-mediated Th cell development. Later during infection, IL-23, a heterodimer composed of the IL-12p40 subunit and the IL-12p35-related molecule p19, preferentially acts on Th1 effector/memory CD4+ T cells. The IL-12p40 subunit can also form a homodimer, IL-12p80, which act as an IL-12 and IL-23 antagonist by competing at their receptors. This review focuses on these IL-12-related cytokines contributing to fine tuning of T cell responses after infection with intracellular pathogens.