Dysregulation of Thymic Clonal Deletion and the Escape of Autoreactive T Cells

Abstract

Events ongoing in the thymus are critical for deleting developing thymocytes specific for tissue antigens, and establishing self-tolerance within the T cell compartment. Aberrant thymic negative selection, however, is believed to generate a repertoire with increased self-reactivity, which in turn can contribute to the development of T cell-mediated autoimmunity. In this review, mechanisms that regulate the efficacy of negative selection and influence the deletion of autoreactive thymocytes will be discussed.

Maturation and Migration of Murine Cd4 Single Positive Thymocytes and Thymic Emigrants

“…Medullary thymic epithelial cells (mTECs) and medullary dendritic cells (mDCs) are two main antigen presenting cells (APCs) in the thymus (Figure 1) [3, 44]. mTECs express a variety of tissue specific antigens (TSA) normally found in the periphery.…”

“…Increasing evidence suggests that the role of Aire is not limited to the regulation of TSA expression. Aire also affects antigen processing by mTECs as well as appropriate differentiation of mTECs [44]. NF-κB signaling plays an important role in regulating Aire expression and mTEC maturation.…”

Maturation and Emigration of Single-Positive Thymocytes

“…The phosphorylated RNAPII is then competent for elongation and cotranscriptional processing of target genes, leading to the expression of TSAs and their presentation to T cells via MHC [65, 66]. In addition to the regulation of TSA expression and tolerance induction, the antigen processing in mTECs can also be affected by Aire [67]. Notably, Aire is also involved in the regulation of thymocyte and dendritic cell migration.…”

Targeting Th17 and Treg Signaling Pathways in Autoimmunity

“…In healthy individuals, the end result of T cell ontogeny is an army of mature naïve T cells, each expressing an individualized T cell antigen receptor (TCR) that will recognize unique danger signals in the form of microbe-derived protein fragments (i.e., antigens), while ignoring those from host tissues or commensal microorganisms. However, even in healthy individuals, a small number of self-reactive T cells can, and do, escape the thymus [3]. In response, nature has evolved a failsafe mechanism to ensure that T cell tolerance toward host tissues is maintained, involving the parallel development of T regulatory (Treg) cells.…”