Positive Selection of Thymocytes

Abstract

Differentiation of alpha beta T cell receptor (TCR)-expressing T cells involves an obligatory interaction with self-major histocompatibility complex (MHC) molecules in the thymus. This process, called positive selection, both rescues thymocytes from programmed cell death and induces their differentiation into mature T cells. Another critical event in thymic development is to prevent maturation of hazardous autoreactive T cells; thus, mechanisms exist to eliminate T cells with self-reactive receptors (negative selection). How can these two pathways be distinguished? This question, which has long taxed immunologists, is more opposite because many features of the interactions in positive and negative selection are shared: Both processes are exquisitely MHC-allele specific, they involve MHC-bound peptide recognition, and employ at least some overlapping signal transduction pathways. However, resolution of this paradox has become much more feasible with the advent of powerful systems for withdrawing and reconstituting individual components involved in positive selection. This review describes recent advances in our understanding of the cells, receptors, ligands, and signaling pathways involved in this process. A pivotal part of this puzzle is the basis for discrimination between TCR ligands that induce positive vs negative selection. Recent work suggests that the peptide/MHC ligand for positive selection may bind with low avidity to the TCR. The implications of these data for the nature of T cell recognition during positive selection are discussed below.

Pharmacologic suppression of target cell recognition by engineered T cells expressing chimeric T-cell receptors

“…15 A high-avidity interaction leads to negative selection, whereas a lowavidity one leads to positive selection. 16 Although additional studies with ex vivo-modified HSCs are necessary, our results suggest that by varying the surface density of the chTCR (intermittent administration of tetracycline), it could be feasible to avoid the negative selection of genemodified HSC-derived precursor cells or even to transform a negative-selecting ligand into a positive-selecting one.…”

Apoptosis in the development of the immune system

“…28,29 T-lymphocyte progenitors that express a functional receptor are further subjected to both positive and negative selection to ensure that a functional receptor exists while eliminating those cells with self-reactive antigen receptors, which could be dangerous due to the potential for autoimmunity ( Figure 3). 30 When the avidity of interaction of the TCR and endogenous major histocompatibility complex (MHC) molecules is low, T-cell progenitors fail to be positively selected and undergo apoptosis. Conversely, in self-reactive T-cells, the avidity between the TCR and MHC is too high; such T-cells are eliminated by negative selection.…”

CD28 Signal Enhances Apoptosis of CD8 T Cells After Strong TCR Ligation

“…We used 2C CD28 wild-type and 2C CD28-deficient strains to assess the effects of CD28 and TCR avidity on peripheral T cell expansion and apoptosis. We compared the activation, division, expansion, and apoptosis of CD28 ؉/؉ and CD28 ؊ T he strength of TCR avidity for antigenic peptides strictly regulates T cell fate in the thymus (1,2). T cell precursors with TCRs that bind self-peptide/MHC complexes with low avidity are selected to survive and further mature.…”