Differences in the level of expression of class I major histocompatibility complex proteins on thymic epithelial and dendritic cells influence the decision of immature thymocytes between positive and negative selection

Abstract

Both positive and negative selection of immature T cells rely on engagement of their antigen-specific receptors (TCR) by peptide in association with proteins encoded in the major histocompatibility complex (MHC) protein. The decision made between these two outcomes seems to be determined by the number of TCR engaged by peptide-MHC complexes. It has been unclear how such a mechanism can be reconciled with evidence that positive and negative selection occur in different thymic compartments and are mediated by different antigen-presenting cells (APCs). In this study we demonstrate that the level of class I MHC protein is 10-fold higher on thymic dendritic cells, which mediate the negative selection of immature T cells, than on thymic epithelial cells, which mediate for positive selection. We also demonstrate that as little as a 3-fold increase in the level of a particular cognate peptide-MHC ligand is sufficient to result in negative rather than positive selection. The results suggest that quantitative differences in the level of expression of class I MHC proteins on thymic epithelial and dendritic cells contribute to the opposing roles these cells play in forming the repertoire of mature class I MHC restricted (CD8 ؉ ) T cells.Studies of T cell development indicate that T cell maturation in the thymus is largely driven by the extent to which antigenspecific receptors (T cell receptors or TCR) on immature thymocytes are engaged by peptide-major histocompatibility complex (MHC) complexes on thymic antigen-presenting cells (APCs; ref. 1). When TCR interact with complexes that are present at relatively low levels, the corresponding thymocytes are stimulated to proceed along the maturation pathway (positive selection); if, however, the complexes are relatively abundant the thymocytes undergo cell death (negative selection). The thymic APCs also have been the subject of many studies. Most reports indicate that positive selection is promoted by thymic epithelial cells whereas negative selection is mediated largely by hemopoietic dendritic cells (DC; ref. 2). Studies of thymocyte maturation in the absence of thymic DC indicate that some T cells can be positively selected by the thymic epithelial cells even when they would otherwise be negatively selected by DC (3). In an attempt to understand the basis for the different outcomes mediated by thymic epithelial and dendritic cells, we used reaggregated thymic organ cultures to investigate cellular requirements for the selection of T cells that express the antigen-specific receptor (TCR) of the CD8 ϩ CTL clone known as 2C.The 2C (6), and the 2C CTL line was also found to recognize the p2Ca peptide in association with K b , albeit weakly (7,8). More recently another naturally processed peptide, EQYKFYSV (dEV8), that can be recognized weakly in association with K b by the 2C TCR has been identified (9).In this study we followed the transition of double-positive (CD4 ϩ , CD8

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

“…The regulation of expression of MHC class I genes is important during development (40,41), differentiation (42), and infection (1, 2), because of the requirement for class I complexes in T cell development and immune recognition of pathogen-infected cells (43). Thus, it might be expected that the genes encoding proteins essential for peptide production and transport as well as for class I complex assembly are coordinately regulated.…”

Stage-dependent reactivity of thymocytes to self-peptide–MHC complexes

“…2 and data not shown) (14) and (ii) there are differences in the intensity with which various TCRs react with self-pMHC complexes. Thus, 2C T cells and thymocytes recognize ubiquitously expressed mitochondrial peptide-K b complexes (35)(36)(37)(38), and, like male-specific HY TCR ϩ cells in male mice (39), they may be more reactive with self-pMHC than T cells that express other TCR transgenes (5).…”

Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

“…MHC I expression levels on TEC have been shown to be critical in the selection of CD8 ϩ thymocytes in mice, with small (1.5-fold) increases in MHC I expression leading to negative rather than positive selection in TCR transgenic models of thymic selection (33). To determine whether such an alteration in thymic selection might occur in the HIV-1-infected human thymus, the expression of CD3, CD4, and CD8 was monitored on mature CD4 ϩ CD8 Ϫ (SP4) and SP8 thymocytes from mock-and HIV-1-infected thymi.…”