Role of thymic cortex-specific self-peptides in positive selection of T cells (original) (raw)
Related papers
International Immunology, 2000
Experiments with synthetic antigen peptides have suggested that a critical parameter that determines the developmental fate of an immature thymocyte is the affinity of interaction between TCR and self-peptide/MHC expressed on thymic stromal cells. To test the physiological relevance of this model for thymocyte development, we determined the affinity of the anti-HY TCR (B6.2.16) expressed on CD8 ⍣ cells for thymic self-peptide/H-2D b tetramers, then examined the ability of these self-peptides to determine the outcome of B6.2.16 CD8 cell selection in the thymus. The B6.2.16 TCR bound the male HY self-antigen with high affinity. Thymic self-peptides, which are highly abundant on the surface of thymic epithelial cells, bound the B6.2.16 TCR with low affinity. The ability of self-peptides to trigger positive or negative selection of B6.2.16 CD8 cells in cultured fetal thymi was determined by the relative affinity of self-peptide/H-2D b for the B6.2.16 TCR. Highaffinity binding of the HY self-peptide resulted in B6.2.16 TCR complex ζ chain phosphorylation and the negative selection of B6.2.16 CD8 cells. Low-affinity binding of thymic self-peptides to B6.2.16 TCR resulted in the positive selection of B6.2.16 CD8 cells. Differences between the binding affinities of self-peptides to B6.2.16 TCR accounted for the self-peptide specificity of B6.2.16 CD8 cell positive selection. We conclude that the relative affinity of TCR for thymic selfpeptide/class I MHC is a critical parameter in determining fate of CD8 ⍣ cells during thymic selection.
Immunity, 1999
tive transfer experiments with CD8 ϩ cells from MHC class I (H2-D b )-reactive HY TCR transgenic mice showed that CD8 ϩ cells survived well in H2-D bϩ hosts but disappeared rapidly in H2-D bϪ mice. The above findings imply that survival of mature naive CD4 ϩ and CD8 ϩ T cells requires continuous, albeit covert, signaling through the TCR. In support of this idea, Summary T cells deficient in a Kruppel-like zinc finger transcription factor designated lung Kruppel-like factor (LKLF) were Positive selection to self-MHC/peptide complexes has found to have a very short life span (Kuo et al., 1997). long been viewed as a device for skewing the T cell Interestingly, LKLF Ϫ embryonic stem cells led to normal repertoire toward recognition of foreign peptides pre-T cell development in the thymus but to the appearance sented by self-MHC molecules. Here, we provide eviof only a few mature T cells in the periphery, because dence for an alternative possibility, namely, that the the T cells underwent spontaneous activation and died self-peptides controlling positive selection in the thyrapidly from Fas-mediated apoptosis. LKLF thus apmus serve to maintain the longevity of mature T cells pears to be involved in translating the low-level TCR in the periphery. Surprisingly, when total T cell numsignaling received from contact with self-MHC molebers are reduced, these self-ligands become overtly cules into signals for mature T cells to persist in the stimulatory and cause naive T cells to proliferate and quiescent state. undergo homeostatic expansion.
Shaping of the Autoreactive Regulatory T Cell Repertoire by Thymic Cortical Positive Selection
The Journal of Immunology, 2007
The main function of regulatory T lymphocytes is to keep autoimmune responses at bay. Accordingly, it has been firmly established that the repertoire of CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells (Tregs) is enriched in autospecific cells. Differences in thymic-positive and/or -negative selection may account for selection of the qualitatively distinct regulatory and conventional T cell (Tconv) repertoires. It has previously been shown that precursors for Tregs are less sensitive to negative selection than Tconv precursors. Studies with TCR/ligand doubly transgenic mice suggested that an agonist ligand might induce positive selection of Treg (but not Tconv) cells. However, massive deletion of Tconv (but not Treg) cell precursors observed in these mice renders interpretation of such data problematic and a potential role for positive selection in generation of the autospecific Treg repertoire has remained therefore incompletely understood. To study this important unresolved issue and circumvent use of TCR/ligand-transgenic mice, we have developed transgenic mice expressing a single MHC class II/peptide ligand on positively selecting thymic cortical epithelial cells. We found that functional Treg (but not Tconv) cells specific for the single ligand were preferentially selected from the naturally diverse repertoire of immature precursors. Our data therefore demonstrate that thymic cortical positive selection of regulatory and Tconv precursors is governed by distinct rules and that it plays an important role in shaping the autoreactive Treg repertoire.
Rare, Structurally Homologous Self-Peptides Promote Thymocyte Positive Selection
Immunity, 2002
Division of Immunology ligands involved in positive selection would be low-affinity nonstimulatory ligands (Lo and Sprent, 1986). Several reports suggested that subthreshold densities of a stimulatory peptide/MHC ligand were capable of promoting ture, were functionally altered (Girao et al., 1997; Kraj et al., 2001a; Sebzda et al., 1996). Peptides that antagonize Center for Immunology University of Minnesota mature T cell responses were also able to induce positive selection in fetal thymus organ cultures (FTOC) MMC 334 420 Delaware Street SE (Hogquist et al., 1994; Jameson et al., 1994; Smyth et al., 1998) and in vivo (Stefanski et al., 2001). However, Minneapolis, Minnesota 55455 5 Biomedical Mass Spectrometry and Functional others have shown that the presence of an antagonist peptide failed to promote (Basu et al., 1998; Williams et Proteomics Facility and Department of Biochemistry and Molecular Biology al., 1996) or impaired positive selection (Kraj et al., 2001a; Spain et al., 1994). Finally, three studies showed Mayo Clinic Rochester, Minnesota 55905 that apparently unrelated peptide/MHC complexes were able to induce positive selection (Ignatowicz et al., 1997; Nakano et al., 1997; Pawlowski et al., 1996). However, all of these studies suffer from the same drawback: Summary while they describe ligands that can promote positive selection in experimental situations, they may not accu-Although it is clear that positive selection of T cells rately reflect the properties of the natural self-peptide/ involves recognition of specific self-peptide/MHC com-MHC ligands that drive positive selection in vivo. plexes, the nature of these self-ligands and their rela-We identified a naturally occurring self-peptide (pretionship to the cognate antigen are controversial. Here viously called CP␣1 but hereafter referred to as we used two complementary strategies to identify nat-Cappa1 92-99 ) that induced positive selection of the OT-I urally occurring self-peptides able to induce positive TCR (Hogquist et al.,
2021
Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced T cell receptor (TCR) sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity downregulate TCR sensitivity more slowly during positive selection, and associate membrane ion channel expression with thymocyte self-reactivity and progress through positive selection.
T cell self-reactivity during thymic development dictates the timing of positive selection
eLife
Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced T cell receptor (TCR) sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity downregulate TCR sensitivity more slowly during positive selection, and associate membrane ion ...
Cell, 1989
During T cell development, the processes of selection and tolerance act on the universe of expressed T cell receptors in the thymic cortex to form the repertoire of mature T cells that will respond to foreign antigen in the context of self-MHC in that animal. We have subdivided the cortical thymocytes into three functionally distinct populations: one population which is antigenreceptor negative, a second population which is antigen-receptor positive and is resistant to deletion by signaling through the antigen receptor, and a third population which is also antigen-receptor positive but is sensitive to deletion. These results have implications for the cellular compartments in which positive and negative selection occur and for the biochemical mechanisms that mediate selection and tolerance.
Thymic Selection Generates a Large T Cell Pool Recognizing a Self-Peptide in Humans
Journal of Experimental Medicine, 2002
The low frequency of self-peptide-specific T cells in the human preimmune repertoire has so far precluded their direct evaluation. Here, we report an unexpected high frequency of T cells specific for the self-antigen Melan-A/MART-1 in CD8 single-positive thymocytes from human histocompatibility leukocyte antigen-A2 healthy individuals, which is maintained in the peripheral blood of newborns and adults. Postthymic replicative history of Melan-A/MART-1specific CD8 T cells was independently assessed by quantifying T cell receptor excision circles and telomere length ex vivo. We provide direct evidence that the large T cell pool specific for the self-antigen Melan-A/MART-1 is mostly generated by thymic output of a high number of precursors. This represents the only known naive self-peptide-specific T cell repertoire directly accessible in humans.