Development of T‐cell tolerance utilizes both cell‐autonomous and cooperative presentation of self‐antigen

Abstract

The development of T cell self-tolerance in the thymus is important for establishing immune homeostasis and preventing autoimmunity. Here, we review the components of T cell tolerance, which includes TCR self-reactivity, costimulation, cytokines, and antigen presentation by a variety of APCs subsets. We discuss the current evidence on the process of regulatory T (Treg) cell and negative selection and the importance of TCR signaling. We then examine recent evidence showing unique roles for bone marrow (BM)-derived APCs and medullary thymic epithelial cells (mTECs) on the conventional and Treg TCR repertoire, as well as emerging data on the role of B cells in tolerance. Finally, we review the accumulating data that suggest that cooperative antigen presentation is a prominent component of T cell tolerance. With the development of tools to interrogate the function of individual APC subsets in the medulla, we have gained greater understanding of the complex cellular and molecular events that determine T cell tolerance.

Broad and Largely Concordant Molecular Changes Characterize Tolerogenic and Immunogenic Dendritic Cell Maturation in Thymus and Periphery

“…Central tolerance occurs in the thymus, where developing T cells encounter ubiquitous self-antigens as well as self-antigens normally found in differentiated tissues outside of the thymus and ectopically expressed by medullary thymic epithelial cells (mTECs) (Klein et al, 2014). In the medulla, developing T cells can recognize such self-antigens directly on mTECs or after transfer to thymic DCs (tDCs) (Perry and Hsieh, 2016), and those with excessive self-reactivity are deleted or deviated into regulatory T (Treg) cells. Central tolerance is incomplete because not all peripheral self-antigens are presented in the thymus.…”

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

“…The development of Tregs in the thymus requires intermediate strength interactions between TCRs and self-peptide/MHC ligands and costimulatory signals delivered by CD28 and members of the tumor necrosis factor receptor superfamily (5,6). These signals lead to the upregulation of the high-affinity IL-2 receptor (IL-2R) α chain (CD25).…”

Immunological Intolerance and Tolerance by Antigenic Co-Stimulation

“…Central tolerance comprises both primary immune sites and immune-privileged tissues, which are often involved in the processes of clonal deletion, anergy, MHC restriction, receptor editing, and other immune tolerogenic processes [8]. In contrast, peripheral tolerance is an adaptive response mediated primarily by immunosuppressive cells (through cell-to-cell contact and production of anti-inflammatory molecules).…”