T cell receptor (TCR)-induced death of immature CD4+CD8+ thymocytes by two distinct mechanisms differing in their requirement for CD28 costimulation: implications for negative selection in the thymus - PubMed (original) (raw)
T cell receptor (TCR)-induced death of immature CD4+CD8+ thymocytes by two distinct mechanisms differing in their requirement for CD28 costimulation: implications for negative selection in the thymus
J A Punt et al. J Exp Med. 1997.
Abstract
Negative selection is the process by which the developing lymphocyte receptor repertoire rids itself of autoreactive specificities. One mechanism of negative selection in developing T cells is the induction of apoptosis in immature CD4+CD8+ (DP) thymocytes, referred to as clonal deletion. Clonal deletion is necessarily T cell receptor (TCR) specific, but TCR signals alone are not lethal to purified DP thymocytes. Here, we identify two distinct mechanisms by which TCR-specific death of DP thymocytes can be induced. One mechanism requires simultaneous TCR and costimulatory signals initiated by CD28. The other mechanism is initiated by TCR signals in the absence of simultaneous costimulatory signals and is mediated by subsequent interaction with antigen-presenting cells. We propose that these mechanisms represent two distinct clonal deletion strategies that are differentially implemented during development depending on whether immature thymocytes encounter antigen in the thymic cortex or thymic medulla.
Figures
Figure 1
TCR-independent and TCR-dependent mechanisms of DP thymocyte apoptosis. Antibodies against cell surface molecules that possess costimulatory/coactivating activity and antibodies against TNFR family members were assessed for their ability to induce apoptosis of rigorously purified DP thymocytes. Control EtBr percentages ranged between 18 and 30% in all experiments presented in this report. (a) Only TNF-α and fas induce death of DP thymocytes in the absence of TCR stimulation. DP thymocytes isolated from young adult female B6 mice were stimulated by platebound antibodies or by 100 ng/ml recombinant murine TNF-α. Cells were harvested after overnight incubation and percent cell death was quantitated by EtBr staining (see Materials and Methods). (b) Only CD28 cooperates with TCR to induce death of DP thymocytes. Cells were stimulated by platebound antibody combinations as indicated. Anti–TCR-β (H5-597) was plated at a concentration of 10 μg/ml. Even though anti-CD28 antibody was unique in its ability to induce cell death, every experimental antibody enhanced TCR-mediated upregulation of CD5 (data not shown). In a and b, each experimental antibody (other than anti-CD28) was plated at both 10 and 50 μg/ml concentrations. Results from the 10 μg/ml plating preparations are shown and were indistinguishable from results with 50 μg/ml concentrations. Cells were harvested and percent cell death was quantitated by EtBr staining (Materials and Methods).
Figure 1
TCR-independent and TCR-dependent mechanisms of DP thymocyte apoptosis. Antibodies against cell surface molecules that possess costimulatory/coactivating activity and antibodies against TNFR family members were assessed for their ability to induce apoptosis of rigorously purified DP thymocytes. Control EtBr percentages ranged between 18 and 30% in all experiments presented in this report. (a) Only TNF-α and fas induce death of DP thymocytes in the absence of TCR stimulation. DP thymocytes isolated from young adult female B6 mice were stimulated by platebound antibodies or by 100 ng/ml recombinant murine TNF-α. Cells were harvested after overnight incubation and percent cell death was quantitated by EtBr staining (see Materials and Methods). (b) Only CD28 cooperates with TCR to induce death of DP thymocytes. Cells were stimulated by platebound antibody combinations as indicated. Anti–TCR-β (H5-597) was plated at a concentration of 10 μg/ml. Even though anti-CD28 antibody was unique in its ability to induce cell death, every experimental antibody enhanced TCR-mediated upregulation of CD5 (data not shown). In a and b, each experimental antibody (other than anti-CD28) was plated at both 10 and 50 μg/ml concentrations. Results from the 10 μg/ml plating preparations are shown and were indistinguishable from results with 50 μg/ml concentrations. Cells were harvested and percent cell death was quantitated by EtBr staining (Materials and Methods).
Figure 2
TCR-CD28 killing of DP thymocytes is not mediated by fas-fasL or TNF-TNFR interactions. DP thymocytes were isolated from the mice indicated (wild-type B6, gld/gld (fasL deficient), lpr/lpr (fas deficient), TNFR (p55)–deficient, and TNFR (p55 and p75)–deficient mice strains. Single-cell suspensions were stimulated overnight by platebound anti–TCR-β and anti-CD28 antibodies, and then were harvested and stained with EtBr. To compare thymocyte apoptosis from different mouse strains with different internal controls, we have normalized individual responses to their respective controls. The normalized value is referred to as a killing index.
Figure 3
Only TCR-CD28–stimulated DP thymocytes die in response to TCR-CD28 coengagement. (a) TCR-CD28 stimulation will not kill bystander CD28 KO DP thymocytes. Individual populations of DP thymocytes from wild-type B6 mice and CD28 KO mice were cultured and stimulated independently with platebound antibodies. % Cell death of each population of DP thymocytes was quantitated and normalized as described in Materials and Methods. (b) Experimental design. DP thymocytes from wild-type mice (CD28+Ly5.2+) were mixed in a 1:1 ratio with DP thymocytes from CD28-deficient mice (CD28−/−Ly 5.1+) and stimulated by platebound anti–TCR-β and anti-CD28. Thymocytes were harvested after overnight culture and percent cell death in each population was determined. CD28+/+ and CD28−/− DP thymocytes were distinguished by the presence or absence of Ly5.1 staining. (c) Bystander CD28 KO DP thymocytes are not killed by TCR-CD28 signals. DP thymocytes were isolated from wild-type and CD28-deficient (CD28 KO) mice which differed in Ly5 expression such that wild-type DP thymocytes were Ly5.2+ and CD28 KO thymocytes were Ly5.1+. Harvested cells were stained with both anti-Ly5.1 antibody and EtBr to determine cell death in each population of cocultured DP thymocytes. Percent cell death was quantitated and normalized as described in Materials and Methods. (d) Schematic of the mechanism by which TCR-CD28 coengagement kills DP thymocytes. This figure illustrates two possible CD28-dependent mechanisms of TCR-mediated apoptosis of DP thymocytes, both of which result in death exclusively of TCR-CD28–stimulated DP thymocytes. The upper figure (i) illustrates one scenario in which simultaneous coengagement of TCR and CD28 molecules directly and cell-autonomously induces an apoptotic program. The lower figure (ii) illustrates an alternative scenario in which simultaneous coengagement of TCR and CD28 induces expression of a death domain containing receptor (Y) that signals apoptosis upon interaction with its ligand (Y-L, Y ligand) that is also expressed on DP thymocytes. In this latter case, the ligand could conceivably engage the death receptor in either cis or trans.
Figure 3
Only TCR-CD28–stimulated DP thymocytes die in response to TCR-CD28 coengagement. (a) TCR-CD28 stimulation will not kill bystander CD28 KO DP thymocytes. Individual populations of DP thymocytes from wild-type B6 mice and CD28 KO mice were cultured and stimulated independently with platebound antibodies. % Cell death of each population of DP thymocytes was quantitated and normalized as described in Materials and Methods. (b) Experimental design. DP thymocytes from wild-type mice (CD28+Ly5.2+) were mixed in a 1:1 ratio with DP thymocytes from CD28-deficient mice (CD28−/−Ly 5.1+) and stimulated by platebound anti–TCR-β and anti-CD28. Thymocytes were harvested after overnight culture and percent cell death in each population was determined. CD28+/+ and CD28−/− DP thymocytes were distinguished by the presence or absence of Ly5.1 staining. (c) Bystander CD28 KO DP thymocytes are not killed by TCR-CD28 signals. DP thymocytes were isolated from wild-type and CD28-deficient (CD28 KO) mice which differed in Ly5 expression such that wild-type DP thymocytes were Ly5.2+ and CD28 KO thymocytes were Ly5.1+. Harvested cells were stained with both anti-Ly5.1 antibody and EtBr to determine cell death in each population of cocultured DP thymocytes. Percent cell death was quantitated and normalized as described in Materials and Methods. (d) Schematic of the mechanism by which TCR-CD28 coengagement kills DP thymocytes. This figure illustrates two possible CD28-dependent mechanisms of TCR-mediated apoptosis of DP thymocytes, both of which result in death exclusively of TCR-CD28–stimulated DP thymocytes. The upper figure (i) illustrates one scenario in which simultaneous coengagement of TCR and CD28 molecules directly and cell-autonomously induces an apoptotic program. The lower figure (ii) illustrates an alternative scenario in which simultaneous coengagement of TCR and CD28 induces expression of a death domain containing receptor (Y) that signals apoptosis upon interaction with its ligand (Y-L, Y ligand) that is also expressed on DP thymocytes. In this latter case, the ligand could conceivably engage the death receptor in either cis or trans.
Figure 3
Only TCR-CD28–stimulated DP thymocytes die in response to TCR-CD28 coengagement. (a) TCR-CD28 stimulation will not kill bystander CD28 KO DP thymocytes. Individual populations of DP thymocytes from wild-type B6 mice and CD28 KO mice were cultured and stimulated independently with platebound antibodies. % Cell death of each population of DP thymocytes was quantitated and normalized as described in Materials and Methods. (b) Experimental design. DP thymocytes from wild-type mice (CD28+Ly5.2+) were mixed in a 1:1 ratio with DP thymocytes from CD28-deficient mice (CD28−/−Ly 5.1+) and stimulated by platebound anti–TCR-β and anti-CD28. Thymocytes were harvested after overnight culture and percent cell death in each population was determined. CD28+/+ and CD28−/− DP thymocytes were distinguished by the presence or absence of Ly5.1 staining. (c) Bystander CD28 KO DP thymocytes are not killed by TCR-CD28 signals. DP thymocytes were isolated from wild-type and CD28-deficient (CD28 KO) mice which differed in Ly5 expression such that wild-type DP thymocytes were Ly5.2+ and CD28 KO thymocytes were Ly5.1+. Harvested cells were stained with both anti-Ly5.1 antibody and EtBr to determine cell death in each population of cocultured DP thymocytes. Percent cell death was quantitated and normalized as described in Materials and Methods. (d) Schematic of the mechanism by which TCR-CD28 coengagement kills DP thymocytes. This figure illustrates two possible CD28-dependent mechanisms of TCR-mediated apoptosis of DP thymocytes, both of which result in death exclusively of TCR-CD28–stimulated DP thymocytes. The upper figure (i) illustrates one scenario in which simultaneous coengagement of TCR and CD28 molecules directly and cell-autonomously induces an apoptotic program. The lower figure (ii) illustrates an alternative scenario in which simultaneous coengagement of TCR and CD28 induces expression of a death domain containing receptor (Y) that signals apoptosis upon interaction with its ligand (Y-L, Y ligand) that is also expressed on DP thymocytes. In this latter case, the ligand could conceivably engage the death receptor in either cis or trans.
Figure 3
Only TCR-CD28–stimulated DP thymocytes die in response to TCR-CD28 coengagement. (a) TCR-CD28 stimulation will not kill bystander CD28 KO DP thymocytes. Individual populations of DP thymocytes from wild-type B6 mice and CD28 KO mice were cultured and stimulated independently with platebound antibodies. % Cell death of each population of DP thymocytes was quantitated and normalized as described in Materials and Methods. (b) Experimental design. DP thymocytes from wild-type mice (CD28+Ly5.2+) were mixed in a 1:1 ratio with DP thymocytes from CD28-deficient mice (CD28−/−Ly 5.1+) and stimulated by platebound anti–TCR-β and anti-CD28. Thymocytes were harvested after overnight culture and percent cell death in each population was determined. CD28+/+ and CD28−/− DP thymocytes were distinguished by the presence or absence of Ly5.1 staining. (c) Bystander CD28 KO DP thymocytes are not killed by TCR-CD28 signals. DP thymocytes were isolated from wild-type and CD28-deficient (CD28 KO) mice which differed in Ly5 expression such that wild-type DP thymocytes were Ly5.2+ and CD28 KO thymocytes were Ly5.1+. Harvested cells were stained with both anti-Ly5.1 antibody and EtBr to determine cell death in each population of cocultured DP thymocytes. Percent cell death was quantitated and normalized as described in Materials and Methods. (d) Schematic of the mechanism by which TCR-CD28 coengagement kills DP thymocytes. This figure illustrates two possible CD28-dependent mechanisms of TCR-mediated apoptosis of DP thymocytes, both of which result in death exclusively of TCR-CD28–stimulated DP thymocytes. The upper figure (i) illustrates one scenario in which simultaneous coengagement of TCR and CD28 molecules directly and cell-autonomously induces an apoptotic program. The lower figure (ii) illustrates an alternative scenario in which simultaneous coengagement of TCR and CD28 induces expression of a death domain containing receptor (Y) that signals apoptosis upon interaction with its ligand (Y-L, Y ligand) that is also expressed on DP thymocytes. In this latter case, the ligand could conceivably engage the death receptor in either cis or trans.
Figure 4
Inhibitors of TCR-CD28–mediated death of DP thymocytes. DP thymocytes from wild-type (B6) mice were stimulated by platebound anti–TCR-β and anti-CD28 in the presence or absence of the following pharmacological agents: the calcineurin inhibitor, cyclosporine A (1 μg/ml); the PI-3-kinase inhibitor, wortmannin (800 ng/ml); the PKCγ inhibitor, GF109203x (800 ng/ml); the protein synthesis inhibitor, cycloheximide (10 μg/ml); and the caspase inhibitor, ZVAD-FMK (100 μM). To compare the effects of various reagents on TCR-CD28–mediated DP thymocyte apoptosis in experiments performed with different solvent controls, individual responses were normalized to their respective controls (killing index). As positive controls for the pharmacologic agents used: cyclosporine A and GF109203x used in this experiment inhibited TCR-mediated CD5 upregulation, and wortmannin used in this experiment blocked NK-mediated target cell lysis (data not shown). Also displayed in the same format are the results of anti–TCR-CD28 stimulation of DP thymocytes isolated from bcl-2 transgenic mice.
Figure 5
Distinct signaling mechanisms of DP thymocyte apoptosis as revealed by differential sensitivity to bcl-2. DP thymocytes isolated from wild-type (B6) and bcl-2 transgenic (bcl-2 TG) mice were cultured with three distinct apoptotic stimuli: dexamethasone (10−6 M), platebound anti-fas antibodies, and platebound anti-TCR and anti-CD28. It can be seen that transgenic bcl-2 expression abrograted TCR-CD28–mediated apoptosis but not fas-mediated apoptosis of DP thymocytes. It might be noted that thymocyte death by TCR-CD28 engagement does not involve glucocorticoids as the steroid inhibitor RU486 only blocked death induced by dexamethasone but not by TCR-CD28 (data not shown).
Figure 6
A CD28-independent mechanism of TCR-mediated death of DP thymocytes. DP thymocytes from either B6 (Ly 5.1+) or CD28 KO (Ly5.1+) mice were co-cultured with Ly 5.2+ APC in the presence or absence of platebound anti-TCR. Harvested cells were stained with both anti-Ly5.1 antibody and EtBr. DP thymocytes were distinguished from APCs by expression of Ly5.1.
Figure 7
CD28-dependent and CD28-independent mechanisms of DP thymocyte apoptosis are distinct. (a) TCR and CD28 signals must be received simultaneously to mediate death of DP thymocytes. DP thymocytes from B6 mice were prestimulated by platebound anti-TCR-β for 6 h. They were then removed from this stimulus and transferred to wells that had been precoated with the antibodies indicated on the x-axis. Cells were harvested and stained with EtBr. The background cell death observed in TCR pretreated groups is likely due to cell damage inflicted by their physical removal from platebound anti-TCR antibody. (b) TCR and second signals derived from APCs do not have to be simultaneous to induce CD28-independent DP thymocyte death. DP thymocytes from CD28 KO (Ly 5.11) mice were prestimulated by platebound anti–TCR-β for 6 h. They were then removed from this stimulus and transferred either into wells that had been precoated with anti-CD28 or into wells containing APCs from B6 Ly5.2 mice (in a 2:1 ratio with the DP cells). Cells were harvested and stained with both Ly5.1 and EtBr. DP thymocytes were distinguished from APC by expression of Ly5.1. As can be seen, preengagement of TCR on DP thymocytes made them susceptible to APC-induced cell death. (c) Schematic of the CD28-independent mechanism of DP thymocyte apoptosis. This figure illustrates the proposed mechanism by which TCR and subsequent APC signals induce apoptosis of DP thymocytes in a CD28-independent manner. TCR prestimulation of DP thymocytes (1) induces upregulation of a molecule X which might express death domains (2). Subsequent engagement of molecule X with a ligand expressed by APCs (X ligand or X-L) induces apoptosis of only prestimulated DP thymocytes (3).
Figure 7
CD28-dependent and CD28-independent mechanisms of DP thymocyte apoptosis are distinct. (a) TCR and CD28 signals must be received simultaneously to mediate death of DP thymocytes. DP thymocytes from B6 mice were prestimulated by platebound anti-TCR-β for 6 h. They were then removed from this stimulus and transferred to wells that had been precoated with the antibodies indicated on the x-axis. Cells were harvested and stained with EtBr. The background cell death observed in TCR pretreated groups is likely due to cell damage inflicted by their physical removal from platebound anti-TCR antibody. (b) TCR and second signals derived from APCs do not have to be simultaneous to induce CD28-independent DP thymocyte death. DP thymocytes from CD28 KO (Ly 5.11) mice were prestimulated by platebound anti–TCR-β for 6 h. They were then removed from this stimulus and transferred either into wells that had been precoated with anti-CD28 or into wells containing APCs from B6 Ly5.2 mice (in a 2:1 ratio with the DP cells). Cells were harvested and stained with both Ly5.1 and EtBr. DP thymocytes were distinguished from APC by expression of Ly5.1. As can be seen, preengagement of TCR on DP thymocytes made them susceptible to APC-induced cell death. (c) Schematic of the CD28-independent mechanism of DP thymocyte apoptosis. This figure illustrates the proposed mechanism by which TCR and subsequent APC signals induce apoptosis of DP thymocytes in a CD28-independent manner. TCR prestimulation of DP thymocytes (1) induces upregulation of a molecule X which might express death domains (2). Subsequent engagement of molecule X with a ligand expressed by APCs (X ligand or X-L) induces apoptosis of only prestimulated DP thymocytes (3).
Figure 7
CD28-dependent and CD28-independent mechanisms of DP thymocyte apoptosis are distinct. (a) TCR and CD28 signals must be received simultaneously to mediate death of DP thymocytes. DP thymocytes from B6 mice were prestimulated by platebound anti-TCR-β for 6 h. They were then removed from this stimulus and transferred to wells that had been precoated with the antibodies indicated on the x-axis. Cells were harvested and stained with EtBr. The background cell death observed in TCR pretreated groups is likely due to cell damage inflicted by their physical removal from platebound anti-TCR antibody. (b) TCR and second signals derived from APCs do not have to be simultaneous to induce CD28-independent DP thymocyte death. DP thymocytes from CD28 KO (Ly 5.11) mice were prestimulated by platebound anti–TCR-β for 6 h. They were then removed from this stimulus and transferred either into wells that had been precoated with anti-CD28 or into wells containing APCs from B6 Ly5.2 mice (in a 2:1 ratio with the DP cells). Cells were harvested and stained with both Ly5.1 and EtBr. DP thymocytes were distinguished from APC by expression of Ly5.1. As can be seen, preengagement of TCR on DP thymocytes made them susceptible to APC-induced cell death. (c) Schematic of the CD28-independent mechanism of DP thymocyte apoptosis. This figure illustrates the proposed mechanism by which TCR and subsequent APC signals induce apoptosis of DP thymocytes in a CD28-independent manner. TCR prestimulation of DP thymocytes (1) induces upregulation of a molecule X which might express death domains (2). Subsequent engagement of molecule X with a ligand expressed by APCs (X ligand or X-L) induces apoptosis of only prestimulated DP thymocytes (3).
Figure 8
Characterization of the CD28-independent mechanism of DP thymocyte apoptosis. DP thymocytes from CD28 KO mice were presetimulated with platebound anti-TCR antibody for 6 h, then cocultured with APC from either gld mice or B6 Ly5.2 mice in the presence or absence of the following reagents: anti-FcR antibody (2.4G2, 10 μg/ml); the fusion protein CD30 Ig (10 μg/ml) which blocks CD30-CD30L interactions; or a combination of anti–B7-1 and anti–B7-2 antibodies (10 μg/ml each) which blocks B7 ligand engagement by both CD28 and CTLA-4. To compare the effects of various reagents on TCR-CD28– mediated DPthymocyte apoptosis in experiments performed over time, individual responses were normalized to their respective controls and the normalized value is referred to as a killing index.
Figure 9
Proposed model of two distinct mechanisms of intrathymic DP clonal deletion. Applying the present data to in vivo thymocyte development, we propose that there are two distinct mechanisms by which autoreactive DP thymocytes are deleted in the thymus. CD28-dependent mechanism (right): DP thymocytes recognizing self-antigens on B7+ cells (i.e., medullary epithelial cells or APCs) are killed by signals generated by simultaneous engagement of TCR and CD28. TCR-CD28 coengagement may directly initiate an apoptotic program (i) or may upregulate a death domain containing receptor that signals death upon interaction with its ligand on DP thymocytes (ii). CD28-independent mechanism (left): DP thymocyte expressing TCR's recognizing self-antigens on cortical epithelium do not die as a consequence of TCR engagement. Instead, they are induced to express a surface molecule (i.e., a death tag, X) that signals them to undergo apoptosis upon subsequent interaction with APC's present in the CMJ. It should be noted that in this model, both mechanisms of clonal deletion of autoreactive DP thymocytes are proposed to occur in the CMJ or medulla even if they encounter self-antigen in the cortex.
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