In the thymus, developing CD4+ T cells that bind strongly to
self-antigen undergo clonal deletion or T-regulatory cell (Treg)
differentiation to establish central self-tolerance. The contributions of
epithelial versus haemopoietic thymic antigen-presenting cells (APCs) to these
two mechanisms are unclear and may vary for self-antigens expressed in
different cell types, in different subcellular locations or at different
abundances. Central tolerance induction was compared in two lines of transgenic
mice expressing the same Aire-dependent membrane-anchored self-antigen at
either high or low levels in thymic epithelial cells. High- or low-level
antigen induced thymocyte deletion at an early or late stage of T-cell
development, respectively. For the high-level antigen, MHCII-deficiency on
haemopoietic APCs caused deletion to occur later in T cell development and
actually enhanced Treg differentiation. By contrast, MHCII-deficiency on
haemopoietic APCs completely abolished central tolerance to low-level
self-antigen. The findings show that highly expressed epithelial
membrane-anchored self-antigen can induce central tolerance via antigen
handover to haemopoietic APCs or via direct presentation by the epithelial
cells themselves, whereas only the former mechanism is available when the same
self-antigen is expressed at low levels. These data provide an explanation for
clinical associations between low expression of membrane-anchored
self-antigens and increased susceptibility to autoimmunity against these
self-antigens.