Unconventional antigen-presenting cells in the induction of peripheral CD8+ T cell tolerance

Bone marrow-derived APCs are considered the predominant cell type involved in the induction and maintenance of T cell tolerance in vivo. In the periphery, cross-presentation of self-antigens by DCs, in particular, CD8alpha(+) DCs, has been the most discussed mechanism underlying the induction of CD8(+) T cell tolerance against self. However, nonhematopoietic APCs in the liver, skin, parenchymal tissues, and lymph nodes can also present self- and exogenous antigens to CD8(+) T cells under steady-state conditions. Although far surpassed by their DC counterparts in their ability to stimulate T cell responses, these unconventional APCs have been shown to play a role in the induction, maintenance, and regulation of peripheral CD8(+) T cell tolerance by a multitude of mechanisms. In this review, we will discuss the different nonhematopoietic cells that have been shown to present tissue-specific or exogenous antigens to naïve CD8(+) T cells, thereby contributing to the regulation of T cell responses in the periphery.