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Cellular and Peptiderequirements for in Vitro Clonal Deletion of Immature

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Cellular and Peptiderequirements for in Vitro Clonal Deletion of Immature Proc. Nati. Acad. Sci. USA Vol. 89, pp. 9000-9004, October 1992 Immunology Cellular and peptide requirements for in vitro clonal deletion of immature thymocytes KAZUYA IWABUCHI*, KEI-ICHI NAKAYAMA*, RODERICK L. McCoy*, FANPING WANG*, TAKASHI NISHIMURAt, SONOKo HABUt, KENNETH M. MURPHYt, AND DENNIS Y. LoH* Departments of *Medicine, Genetics, and Molecular Microbiology, and *Pathology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110; and tDepartment of Immunology, Tokai University School of Medicine, Isehara 259-11, Japan Communicated by Herman N. Eisen, June 23, 1992 (receivedfor review March 16, 1992) ABSTRACT Thymocytes from DO1 T-cell-receptor deletion system that can be used to elucidate the cellular and trasgenic mice undergo apoptosis, or programmed cell death, peptide-antigen requirements for inducing clonal deletion. when chicken ovalbumin-(323-339) peptide is administered in vivo. Using DO1 mice thymocytes, we have now developed a EXPERIMENTAL PROCEDURES simple in vitro model system that recapitulates the in vivo Mice. TCR transgenic mice (DO10) bearing TCR from a clonal-deletion process. When transgenic thymocytes were hybridoma, DO11.10, with specificity for cOVA-(323-339) cocultured with fibroblasts, B cells, or thymic nurse cell lines and I-Ad have been backcrossed to BALB/c mice and are (all bearing I-Ad) in the presence of chicken ovalbumin-(323- maintained in our own animal facility. KA mice were created 339), deletion of the transgenic TCR+CD4+CD8+ thymocytes by the microinjection of I-Ad genes (a and f3) driven by class was seen within 8-20 hr. Thymocytes designed to bear I-Ad on I MHC Kb promoter into mouse embryos and maintained in their surface could mediate the deletion themselves. Thus, the H-2d background (13). thymocyte clonal deletion entirely depends on the stage at Cells. RT2.3.3.HD6, I-Ad-transfected L-cell fibroblasts, which the thymocytes are vulnerable to the onset of apoptosis, was provided by R. Germain (National Institutes of Health, rather than on the nature of the peptide antigen-presenting Bethesda, MD) (14). TNC-R3.1, a thymic nurse cell line from cells. Furthermore, thymic nurse cell line TNC-R3.1 could a AKR/J (H-2k) mouse that shows properties similar to cause deletion, strongly suggesting that some thymic epitheli- thymic nurse cells, was transfected with genomic I-Ad genes al/stromal components are potentially capable ofparticipating (a and is) linked to class I MHC Kb promoter and selected for in negative selection. In all cases examined, little deletion could their cell-surface expression (15). A20 and TA3, B-cell lym- be induqed at a peptide concentration <10 nM, thus defining phoma lines, were obtained from E. Unanue and T. Braciale the minimum amount of peptid& antigen required for negative (Washington University, St. Louis). selection. The peptide-dependent in vitro negative-selection Peptides. Peptides were made by using a model 430 peptide system will allow further dissection of the molecular and synthesizer (Applied Biosystems) and purified by HPLC as cllular processes involved in clonal deletion due to apoptosis in described (16). Peptide sequences are as follows: cOVA- the thymus. (323-339), ISQAVHAAHAEINEAGR, and cOVA-(324- 334), SQAVTAAHAEI (which also has a histidine to threo- Clonal deletion or negative selection of self-reactive T cells nine change at position 328). during thymic development plays a critical role in inducing Flow Cytometry. Lyt-2 fluorescein isothiocyanate (Becton immunological self-tolerance (1-3). With transgenic mice Dickinson), L3T4-phycoerythrin (Becton Dickinson), and bearing T-cell receptor (TCR) of defined peptide antigen biotinylated KJ1-26 (anticlonotypic TCR monoclonal anti- specificity, self-reactive T cells have been shown to undergo body) plus streptavidin-Red613 (GIBCO/BRL) were used. apoptosis, or programmed cell death, during the process of Three-color flow cytometric analysis was done with FAC- clonal deletion in the thymus (4). Thymocytes can thus be Scan (Becton Dickinson). Dead cells were gated out by triggered to undergo apoptosis upon engagement of the TCR staining with propidium iodide at 5 Ag/ml (Sigma) in the FL3 with the peptides presented in the context of the appropriate channel, whereas RT2.3.3.HD6, A20, TA3, and TNC-R3.1 major histocompatibility complex (MHC) molecules. The cells were easily gated out from the thymocytes by using exact nature of the cell-cell interactions or the signaling forward- and side-scatter channels. For experiments with pat ways that precipitate programmed cell death in the T-cell-depleted splenic antigen-presenting cells (APCs), Thy- developing thymocytes is unknown (5-9). Tolerance induc- 1.2-phycoerythrin (PharMingen, San Diego) was used in- tion is thought to largely depend on the antigen-presenting stead of CD4-phycoerythrin to exclude splenic APCs from capability of the bone-marrow-derived cells like macro- the thymocytes by gating on FL2 channel. phages and dendritic cells, whereas the role of thymic epi- In Vitro Deletion Assay. For the adherent APCs (L-cell, theligl/stromal cells is controversial (10-12). However, little RT2.3.3.HD6, and TNC-R3.1), 4 x 106 thymocytes were is known about the amount and form of antigen required to cultured with APCs confluently covering the bottom of a delete the developing thymocytes. We have recently devel- 6-well flat-bottomed tissue culture plate (Costar) in 3 ml of oped a TCR transgenic mouse, DO10, that has a TCR that RPMI 1640 medium/10%o fetal calf serum containing the recognizes a chicken ovalbumin (cOVA) peptide-(323-339) in designated amount of appropriate peptides for the indicated the context of a class II MHC molecule, I-Ad (4). When durations. Thymocytes and APCs were harvested by exten- cOVA-(323-339) was injected i.p. into these mice, the de- sive pipetting in 1.2 mM EDTA/phosphate-buffered saline. veloping, immature thymocytes underwent apoptosis in an Similarly, 1 x 105 nonadherent APCs (A20, TA3, and T-cell- antigen-specific manner. Using these mice, we now report on depleted splenic APCs) and 1 x 106 thymocytes were cultured the development of a simple in vitro thymocyte clonal- in a 96-well round-bottomed tissue-culture plate (Costar) in 0.2 The publication costs of this article were defrayed in part by page charge Abbreviations: APC, antigen-presenting cell; DP, double-positive; payment. This article must therefore be hereby marked "advertisement" TCR, T-cell receptor; cOVA, chicken ovalbumin; MHC, major in accordance with 18 U.S.C. §1734 solely to indicate this fact. histocompatibility complex. 9000 Downloaded by guest on September 29, 2021 Immunology: Iwabuchi et al. Proc. Natl. Acad. Sci. USA 89 (1992) 9001 ml of identical medium. The harvested cells were counted, totic cells were distributed extensively and uniformly stained, and analyzed by FACScan as above. Typical back- throughout the thymic cortex (4). Because these thymocytes ground was 25-30% spontaneous deaths in a 20-hr assay. themselves are I-Ad negative and the macrophage/dendritic Detection ofDNA Fragmentation and EM. Thymocytes and cells reside predominantly in the thymic medulla, the possi- A20 cells were cultured as described, with cOVA-(324-334) bility that other cells in the thymic cortex may cause clonal or cOVA-(323-339) at 1 ttM. Cells were harvested after 5 hr deletion by presenting the cOVA-(323-339) peptide to the because DNA fragmentation can be seen earlier than the cortical thymocytes was raised. One such candidate would be decrease of the CD4+CD8+ population. Fragmented DNA the cortical epithelial/stromal cells that are known to be class was prepared from 5 x 105 thymocytes by the method of I and II MHC positive. To test which cells can provide the Newell et al. (17). Samples were separated by electrophoresis necessary trigger to initiate apoptosis among immature thy- on a 1.5% agarose gel containing ethidium bromide at 0.5 mocytes, an in vitro clonal-deletion system was developed. Ag/ml. For EM, thymocytes and A20 cells were cultured, as Initially, D010 thymocytes were incubated with T-cell- described, with cOVA-(324-334) or cOVA-(323-339) at 1 ;M depleted splenocytes from BALB/c (H-2d) mice with the for 20 hr. Culture medium was aspirated and immediately cOVA peptides. The cells were harvested after 15- to 20-hr replaced by an isotonic 3% (wt/vol) glutaraldehyde solution. incubation with 1 AM cOVA-(323-339); -70-75% of DP Electron micrographs were taken as described (4). thymocytes were deleted, whereas the TCRhiCD4+CD8- (single-positive) cells were unaffected. Clonal deletion was RESULTS AND DISCUSSION not seen when either the cOVA-(323-339) or the APCs were cOVA-(323-339) Deletes TCR+CD4+CD8+ Immature Thy- absent (data not shown). To explore whether other cell types mocytes in Vitro. T cells from the DO10 TCR transgenic mice could induce clonal deletion, an I-Ad-expressing L-cell fibro- respond to cOVA-(323-339) when presented in the context of blast transfectant, RT2.3.3.HD6, was used to present pep- I-Ad and bear the TCR clonotypic marker recognized by the tides (14). Deletion of the KJ1-26+ DP cells was seen upon monoclonal antibody KJ1-26 (18, 19). Upon in vivo admin- incubation with cOVA-(323-339) (Fig. 1A); No such deletion istration of cOVA-(323-339), KJ1-26+ CD4+CD8+ double- was seen with cOVA-(324-334) (Fig. 1A) or with influenza positive (DP) immature thymocytes are preferentially de- nucleoprotein peptide, which does not bind to I-Ad [A/nt/ leted. Because cOVA-(324-334), which binds to I-Ad but 60/68-(345-360), data not shown]. Relatively, the percentage cannot stimulate the transgenic TCR, does not cause dele- of CD4+CD8- and KJ1-26- DP cells increased with cOVA- tion, apoptosis among the DP thymocytes requires the rec- (322-339), but the actual cell numbers remained unchanged ognition ofboth the I-Ad and cOVA-(323-339) by the KJ1-26+ (Fig.
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