A cytotoxic T lymphocyte clone can recognize the same naturally occurring self peptide in association with a self and a nonself class I MHC protein

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Algorithms derived from measurements of short-peptide (8-10 mers) binding to class I MHC proteins suggest that the binding groove of a class I MHC protein, such as K b , can bind well over 1 million different peptides with significant affinity (<500 nM), a level of ligand-binding promiscuity approaching the level of heat shock protein binding of unfolded proteins. MHC proteins can, nevertheless, discriminate between similar peptides and bind many of them with high (nanomolar) affinity. Some insights into this high-promiscuity/high-affinity behavior and its impact on immunodominant peptides in T-cell responses to some infections and vaccination are suggested by results obtained here from testing a model developed to predict the number of cell surface peptide-MHC complexes that form on cells exposed to extracellular (exogenous) peptides.

Section: Sensitivity Of Calculated Numbers Of Mp Per Cell To Changes Inmentioning

confidence: 99%

Promiscuous binding of extracellular peptides to cell surface class I MHC protein

Eisen

Hou

Shen

et al. 2012

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Delaney

Sykulev

Eisen

et al. 1998

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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

“…By constructing transgenic mice expressing the 2C TCR and crossing the TCR transgene onto different H-2 backgrounds, it was shown that the positive selecting MHC for the 2C T cells is K b (16,17). Among the naturally derived peptides recognized by the 2C TCR in association with L d and K bm3 , p2Ca and dEV8 bind weakly to K b and behave as weak agonists (18). However, several strong agonist peptides have been identified in combinatorial libraries to associate with K b and activate the 2C T cells (19).…”

mentioning

confidence: 99%

Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Holler

Mahajan

et al. 2006

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Most ␣␤ T cells belong to one of the two lineages defined by the mutually exclusive expression of CD8 or CD4 coreceptors, which bind MHC class I and class II molecules, respectively. Because the binding of the coreceptors to MHC molecules stabilizes weak interactions between TCRs and peptide-MHC (pMHC) complexes, CD8 ϩ T cells are MHC class I-restricted whereas CD4 ϩ T cells are MHC class II-restricted. The concordance of CD4 or CD8 lineage development with specificity for class I or II MHC is established during differentiation of CD4 ϩ CD8 ϩ double-positive (DP) thymocytes in the thymus by a process referred to as positive selection (4). Whether a DP thymocyte differentiates into a CD4 ϩ or CD8 ϩ T cell depends on differences in TCR signaling as a result of interactions among TCR, coreceptors, and self-peptide-MHC (self-pMHC) complexes (5-8).Many TCRs are known to interact not only with self-but also with foreign MHC molecules (alloreactivity). Among the bestdocumented examples is the recognition of different pMHC complexes by a TCR called 2C (9). The 2C TCR was derived from a CD8 ϩ cytotoxic T lymphocyte (CTL) clone from an H-2 b mouse (BALB.B) that was injected with H-2 d cells (10, 11). The 2C TCR reacts with L d in association with two overlapping peptides QL-SPFPFDL (QL9) and p2Ca derived from ␣-ketoglutarate dehydrogenase (10,12,13). The 2C TCR is also alloreactive to K bm3 in association with the dEV8 peptide derived from NADHubiquinone oxoreductase (14,15). By constructing transgenic mice expressing the 2C TCR and crossing the TCR transgene onto different H-2 backgrounds, it was shown that the positive selecting MHC for the 2C T cells is K b (16,17). Among the naturally derived peptides recognized by the 2C TCR in association with L d and K bm3 , p2Ca and dEV8 bind weakly to K b and behave as weak agonists (18). However, several strong agonist peptides have been identified in combinatorial libraries to associate with K b and activate the 2C T cells (19). Among them, SIYRYYGL (SIY) has been extensively characterized. In addition to recognizing various peptides in association with MHC class I L d , K bm3 , and K b molecules, the 2C TCR was also shown recently to recognize a nonclassical class I molecule, leading to differentiation of CD8 ϩ T cells that home to the intestine during fetal and neonatal development (20).The ability of a given TCR to interact with multiple MHC molecules, especially both class I and class II, can have a significant influence on the development of CD4 versus CD8 T cells. For example, the HY TCR nominally recognizes class I D b for CD8 T cell development but also interacts with class II I-A b for CD4 T cell development (21). Similarly, the HA and AND TCRs nominally interact with class II MHC for CD4 T cell development but also promote the development of CD8 T cells on either the RAG Ϫ/Ϫ or the CD4 Ϫ/Ϫ plus TCR␣ Ϫ/Ϫ background (22, 23). The development of CD8 HA or AND transgenic T cells was shown to require the interaction of the TCRs with both class I and class II MHC molecules....