Intracellular signals that mediate thymic negative selection

Vasquez, Nicki; Kane, Larry; Hedrick, Stephen M.

doi:10.1016/1074-7613(94)90008-6

Cited by 53 publications

(35 citation statements)

References 53 publications

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“…This is because it would make sense to have a lower threshold for deletion of autoreactive clones, thereby providing a safety margin against autostimulation of mature T cells (42). Several studies have demonstrated that thymocytes are indeed more sensitive to stimulation than mature T cells are (42)(43)(44), but in some assays thymocytes are found to be less responsive (45,46). What we have observed is that the relative sensitivity of thymocytes to stimulation depends on the strength of the ligand considered.…”

Section: Kinetic Proofreading In Negative Selectionsupporting

confidence: 55%

Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Kersh

Engle

Williams

et al. 2000

The Journal of Immunology

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Positive and negative selection of thymocytes is determined by the specificity of the TCR and signaling through its associated molecules. We have studied selection of thymocytes bearing a MHC class II-restricted TCR using fetal thymic organ culture. This system allows the addition of peptides to the already diverse panoply of endogenous peptide ligands and is useful for analyzing ligand-specific negative selection of CD4 single positive (CD4SP) thymocytes. The data reveal that the ability of a given ligand to mediate negative selection is related to its dissociation rate from the TCR. We find that negative selection is very sensitive, and only the weakest ligand that we can identify fails to induce negative selection. None of the numerous peptides tested were able to induce an increase in CD4SP thymocytes. In addition, the ligands that induce negative selection of CD4SP thymocytes also cause an increase in numbers of CD8SP thymocytes bearing high levels of the class II-restricted TCR. Although these cells have a cell surface phenotype consistent with positive selection, they most likely represent cells in the process of negative selection. Further analysis reveals that these cells are not induced by these ligands in intact adult animals and that their induction is probably only revealed in the organ culture system.

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Section: Kinetic Proofreading In Negative Selectionsupporting

confidence: 55%

Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Kersh

Engle

Williams

et al. 2000

The Journal of Immunology

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“…However, numerous studies have concluded that DP thymocytes are more sensitive to Ag than SP thymocytes or peripheral T cells (6,7,(31)(32)(33)(34)(35)(36). It seems contradictory, then, to propose that the thymus maintains DP thymocytes in a relatively insensitive state.…”

Section: Discussionmentioning

confidence: 95%

“…Both low receptor expression and constitutive phosphorylation would be expected to inhibit signaling through the TCR on DP thymocytes (5). Nonetheless, these cells can respond efficiently to TCR stimulation, as they undergo deletion at low concentrations of antigenic peptide in vitro (6,7). How these cells show high sensitivity to Ag despite low TCR expression remains unclear.…”

Section: T Cell Development Depends On Engagement Of the Tcr On Cd4mentioning

confidence: 99%

Inefficient Cell Spreading and Cytoskeletal Polarization by CD4+CD8+ Thymocytes: Regulation by the Thymic Environment

Hailman

Allen

2005

The Journal of Immunology

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CD4+CD8+ double-positive (DP) thymocytes express a lower level of surface TCR than do mature T cells or single-positive (SP) thymocytes. Regulation of the TCR on DP thymocytes appears to result from intrathymic signaling, as in vitro culture of these cells results in spontaneous TCR up-regulation. In this study, we examined cell spreading and cytoskeletal polarization responses that have been shown to occur in response to TCR engagement in mature T cells. Using DP thymocytes stimulated on lipid bilayers or nontransgenic thymocytes added to anti-CD3-coated surfaces, we found that cell spreading and polarization of the microtubule organizing center and the actin cytoskeleton were inefficient in freshly isolated DP thymocytes, but were dramatically enhanced after overnight culture. SP (CD4+) thymocytes showed efficient responses to TCR engagement, suggesting that releasing DP thymocytes from the thymic environment mimics some aspects of positive selection. The poor translation of a TCR signal to cytoskeletal responses could limit the ability of DP thymocytes to form stable contacts with APCs and may thereby regulate thymocyte selection during T cell development.

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“…In particular, some analogs were shown to act as TCR antagonists and inhibit T cell responses to the antigenic peptide (13). Several studies have shown that antagonist peptides are capable of positively selecting (9,10), negatively selecting (14,15), or blocking positive selection (16) of thymocytes. However, other studies have found that the ability of a peptide to select thymocytes positively or negatively does not always correlate with its properties as a TCR antagonist (10,11,17,18).…”

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confidence: 99%

Interactions with multiple peptide ligands determine the fate of developing thymocytes

Williams¹,

Tarazona²,

Wack³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Thymocytes are positively or negatively selected depending on interactions between their T cell receptors (TCR) and peptides presented by major histocompatibility complex molecules. We have previously shown that apoptosis of thymocytes from an ␣␤ TCR-transgenic mouse (F5), induced by antigenic peptide, can be inhibited specifically by an antagonist peptide variant in an in vitro culture model. We have now extended these experiments by demonstrating that the antagonist peptide can inhibit natural negative selection of maturing thymocytes, induced by endogenously expressed antigen, in fetal thymic organ cultures (FTOC). This inhibition resulted in the rescue and maturation of thymocytes that would otherwise have been deleted. Mature T cells generated in these cultures were able to respond to antigen by producing limited quantities of interferon-␥, but unlike T cells from control FTOC, they required exogenous interleukin-2 to generate cytolytic effector cells. Interestingly, the antagonist peptide also accelerated the development of F5 thymocytes in the absence of the negatively selecting ligand. These data suggest that the developmental fate of a thymocyte may be determined by the recognition of multiple distinct peptide ligands during thymic selection. Alterations in the profiles of selecting peptides presented in the thymus would thus have profound effects on the size and autoreactive potential of the T cell repertoire generated.T lymphocytes are positively or negatively selected in the thymus as a result of interactions between their T cell receptors (TCR) and thymic peptide-major histocompatibility complexes (MHC) (1-11). Much of the recent work on thymic selection was influenced by experiments that examined T cell responses to peptide analogs, produced from the antigenic peptide by substitution of amino acid residues involved in interaction with the TCR. Such peptide analogs can generate qualitatively different T cell responses compared with those produced by the antigenic peptide (12). In particular, some analogs were shown to act as TCR antagonists and inhibit T cell responses to the antigenic peptide (13). Several studies have shown that antagonist peptides are capable of positively selecting (9, 10), negatively selecting (14, 15), or blocking positive selection (16) of thymocytes. However, other studies have found that the ability of a peptide to select thymocytes positively or negatively does not always correlate with its properties as a TCR antagonist (10,11,17,18).We have previously reported an analog peptide (19) that was capable of inhibiting antigen-specific lysis of target cells by cytotoxic T lymphocyte (CTL) from ␣␤ TCR (F5)-transgenic mice (20,21). Furthermore, this peptide was shown to inhibit apoptosis of transgenic thymocytes (19) in an in vitro suspension culture assay (22). Because the suspension culture could not support the development of immature thymocytes, we could not determine whether this inhibition would result in the rescue and complete maturation of thymocytes. In the pre...

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Intracellular signals that mediate thymic negative selection

Cited by 53 publications

References 53 publications

Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Inefficient Cell Spreading and Cytoskeletal Polarization by CD4+CD8+ Thymocytes: Regulation by the Thymic Environment

Interactions with multiple peptide ligands determine the fate of developing thymocytes

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