Mechanisms of regulatory T cell counter-regulation by innate immunity.

One of the most significant advances in the field of immunology in the last decade is delineation of the pivotal role of regulatory T cells (Tregs) in the maintenance of self-tolerance. While Tregs are just now being applied therapeutically in early phase clinical trials, data gleaned from basic and translational studies to-date suggest enormous potential to intervene in human disease. Data from our work and the work of others suggest that the innate immune system plays an important role in the differentiation and function of Tregs, largely through the production of cytokines but also through expression of cell surface ligands. These molecules are expressed differentially depending on whether the stimulus includes trauma, ischemia/necrosis, and microbial infection, and have opposing effects on Tregs, in contrast to those associated with dendritic cell maturation and somatic cell apoptosis, which promote Treg differentiation and function. We refer to the former process as Treg counter-regulation. Since the transplantation procedure involves surgical trauma, organ ischemia, and exposure to environmental microbes, Treg counter-regulation represents a key area of intervention to improve strategies for promoting allograft tolerance.