© The Rockefeller University Press, 0022-1007/1997/1/263/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 2, January 20, 1997 263-272
Negative Selection in the Thymus Includes Semimature T Cells
Hidehiro Kishimoto and
Jonathan Sprent
From the Department of Immunology, IMM4, The Scripps Research Institute, La Jolla, California 92037
The thymic medulla plays a key role in negative selection (self-tolerance induction) and contains differentiated T cells en route to the extrathymic environment. However, being relatively mature, medullary T cells are thought to be beyond the stage of tolerance induction. This paradox is resolved by the finding that medullary T cells (CD4+8– thymocytes) comprise two distinct subsets. Medullary thymocytes expressing a fully mature (HSAlo) phenotype are strongly resistant to tolerance induction, whereas cells with a semimature (HSAhi) phenotype are tolerance susceptible. These findings suggest that the differentiated T cells reaching the medulla from the cortex remain sensitive to tolerance induction for a brief period before acquiring a fully mature tolerance-resistant phenotype. The semimature subset of medullary T cells displays unique requirements for tolerance induction; depending upon the conditions used, tolerizing these cells can involve either a Fas (CD95)-dependent or a Fas-independent pathway.
Address correspondence to Jonathan Sprent, Department of Immunology, IMM4, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
We wish to express our thanks to Dr. David Lynch and Immunex for providing Fas–Ig and to Ms. Barbara Marchand for typing the manuscript.
This work was supported by grants CA38355, CA25803, AI21487, and AI32068 from the United States Public Health Service. Dr. Hidehiro Kishimoto is the recipient of a fellowship from the Cancer Research Institute. This is publication number 9928-IMM from The Scripps Research Institute.
1Abbreviations used in this paper: AICD, activation-induced cell death; BM, bone marrow; C, constant; DP, double positive; FasL, Fas ligand; HSA, heatstable antigen; PI, propidium iodide; SP, single positive; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling.

CiteULike
Complore
Connotea
Del.icio.us
Digg
Facebook
Reddit
Technorati
Twitter What's this?
This article has been cited by other articles:
-
Wirnsberger, G., Mair, F., Klein, L.
(2009). Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control. Proc. Natl. Acad. Sci. USA
106: 10278-10283
[Abstract]
[Full Text]
-
Trost, B., Kanduc, D., Kusalik, A.
(2009). Rare peptide segments are found significantly more often in proto-oncoproteins than control proteins: implications for immunology and oncology. J R Soc Interface
6: 123-127
[Abstract]
[Full Text]
-
Weinreich, M. A., Hogquist, K. A.
(2008). Thymic Emigration: When and How T Cells Leave Home. J. Immunol.
181: 2265-2270
[Abstract]
[Full Text]
-
Cretney, E., Uldrich, A. P., McNab, F. W., Godfrey, D. I., Smyth, M. J.
(2008). No requirement for TRAIL in intrathymic negative selection. Int Immunol
20: 267-276
[Abstract]
[Full Text]
-
Davalos-Misslitz, A. C. M., Worbs, T., Willenzon, S., Bernhardt, G., Forster, R.
(2007). Impaired responsiveness to T-cell receptor stimulation and defective negative selection of thymocytes in CCR7-deficient mice. Blood
110: 4351-4359
[Abstract]
[Full Text]
-
Burke, B., Brown, H. J., Marsden, M. D., Bristol, G., Vatakis, D. N., Zack, J. A.
(2007). Primary Cell Model for Activation-Inducible Human Immunodeficiency Virus. J. Virol.
81: 7424-7434
[Abstract]
[Full Text]
-
Fragoso, R. C., Pyarajan, S., Irie, H. Y., Burakoff, S. J.
(2006). A CD8/Lck Transgene Is Able to Drive Thymocyte Differentiation. J. Immunol.
177: 6007-6017
[Abstract]
[Full Text]
-
Uldrich, A. P., Berzins, S. P., Malin, M. A., Bouillet, P., Strasser, A., Smyth, M. J., Boyd, R. L., Godfrey, D. I.
(2006). Antigen challenge inhibits thymic emigration.. J. Immunol.
176: 4553-4561
[Abstract]
[Full Text]
-
Romagnoli, P., Hudrisier, D., van Meerwijk, J. P. M.
(2005). Molecular Signature of Recent Thymic Selection Events on Effector and Regulatory CD4+ T Lymphocytes. J. Immunol.
175: 5751-5758
[Abstract]
[Full Text]
-
Bunin, A., Khwaja, F. W., Kersh, G. J.
(2005). Regulation of Bim by TCR Signals in CD4/CD8 Double-Positive Thymocytes. J. Immunol.
175: 1532-1539
[Abstract]
[Full Text]
-
Munitic, I., Williams, J. A., Yang, Y., Dong, B., Lucas, P. J., El Kassar, N., Gress, R. E., Ashwell, J. D.
(2004). Dynamic regulation of IL-7 receptor expression is required for normal thymopoiesis. Blood
104: 4165-4172
[Abstract]
[Full Text]
-
Zhang, Y., Joe, G., Zhu, J., Carroll, R., Levine, B., Hexner, E., June, C., Emerson, S. G.
(2004). Dendritic cell-activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity. Blood
103: 3970-3978
[Abstract]
[Full Text]
-
Koyanagi, M., Imanishi, K.'i., Arimura, Y., Kato, H., Yagi, J., Uchiyama, T.
(2004). Immunologic immaturity, but high IL-4 productivity, of murine neonatal thymic CD4 single-positive T cells in the last stage of maturation. Int Immunol
16: 315-326
[Abstract]
[Full Text]
-
Jung, K. C., Park, W. S., Kim, H. J., Choi, E. Y., Kook, M.-C., Lee, H.-W., Bae, Y.
(2004). TCR-Independent and Caspase-Independent Apoptosis of Murine Thymocytes by CD24 Cross-Linking. J. Immunol.
172: 795-802
[Abstract]
[Full Text]
-
Mayerova, D., Hogquist, K. A.
(2004). Central Tolerance to Self-Antigen Expressed by Cortical Epithelial Cells. J. Immunol.
172: 851-856
[Abstract]
[Full Text]
-
Thien, C. B.F., Scaife, R. M., Papadimitriou, J. M., Murphy, M. A., Bowtell, D. D.L., Langdon, W. Y.
(2003). A Mouse with a Loss-of-function Mutation in the c-Cbl TKB Domain Shows Perturbed Thymocyte Signaling without Enhancing the Activity of the ZAP-70 Tyrosine Kinase. JEM
197: 503-513
[Abstract]
[Full Text]
-
Zhan, Y., Purton, J. F., Godfrey, D. I., Cole, T. J., Heath, W. R., Lew, A. M.
(2003). Without peripheral interference, thymic deletion is mediated in a cohort of double-positive cells without classical activation. Proc. Natl. Acad. Sci. USA
100: 1197-1202
[Abstract]
[Full Text]
-
Cho, H. J., Edmondson, S. G., Miller, A. D., Sellars, M., Alexander, S. T., Somersan, S., Punt, J. A.
(2003). Cutting Edge: Identification of the Targets of Clonal Deletion in an Unmanipulated Thymus. J. Immunol.
170: 10-13
[Abstract]
[Full Text]
-
Brewer, J. A., Kanagawa, O., Sleckman, B. P., Muglia, L. J.
(2002). Thymocyte Apoptosis Induced by T Cell Activation Is Mediated by Glucocorticoids In Vivo. J. Immunol.
169: 1837-1843
[Abstract]
[Full Text]
-
Trimble, L. A., Prince, K. A., Pestano, G. A., Daley, J., Cantor, H.
(2002). Fas-Dependent Elimination of Nonselected CD8 Cells and lpr Disease. J. Immunol.
168: 4960-4967
[Abstract]
[Full Text]
-
Le Campion, A., Lucas, B., Dautigny, N., Leaument, S., Vasseur, F., Penit, C.
(2002). Quantitative and Qualitative Adjustment of Thymic T Cell Production by Clonal Expansion of Premigrant Thymocytes. J. Immunol.
168: 1664-1671
[Abstract]
[Full Text]
-
Li, R., Page, D. M.
(2001). Requirement for a Complex Array of Costimulators in the Negative Selection of Autoreactive Thymocytes In Vivo. J. Immunol.
166: 6050-6056
[Abstract]
[Full Text]
-
Viret, C., Sant'Angelo, D. B., He, X., Ramaswamy, H., Janeway, C. A. Jr.
(2001). A Role for Accessibility to Self-Peptide-Self-MHC Complexes in Intrathymic Negative Selection. J. Immunol.
166: 4429-4437
[Abstract]
[Full Text]
-
Tian, T., Zhang, J., Gao, L., Qian, X. P., Chen, W.-F.
(2001). Heterogeneity within medullary-type TCR{{alpha}}{beta}+CD3+CD4-CD8+ thymocytes in normal mouse thymus. Int Immunol
13: 313-320
[Abstract]
[Full Text]
-
Moore, J. K., Scheinman, R. I., Bellgrau, D.
(2001). The Identification of a Novel T Cell Activation State Controlled by a Diabetogenic Gene. J. Immunol.
166: 241-248
[Abstract]
[Full Text]
-
Hayashi, K., Natsume, W., Watanabe, T., Abe, N., Iwai, N., Okada, H., Ito, Y., Asano, M., Iwakura, Y., Habu, S., Takahama, Y., Satake, M.
(2000). Diminution of the AML1 Transcription Factor Function Causes Differential Effects on the Fates of CD4 and CD8 Single-Positive T Cells. J. Immunol.
165: 6816-6824
[Abstract]
[Full Text]
-
Lucas, B., Germain, R. N.
(2000). Opening a Window on Thymic Positive Selection: Developmental Changes in the Influence of Cosignaling by Integrins and CD28 on Selection Events Induced by TCR Engagement. J. Immunol.
165: 1889-1895
[Abstract]
[Full Text]
-
Ge, Q., Chen, W.-F.
(2000). Effect of murine thymic epithelial cell line (MTEC1) on the functional expression of CD4+CD8- thymocyte subgroups. Int Immunol
12: 1127-1133
[Abstract]
[Full Text]
-
Norian, L. A., Latinis, K. M., Eliason, S. L., Lyson, K., Yang, C., Ratliff, T., Koretzky, G. A.
(2000). The Regulation of CD95 (Fas) Ligand Expression in Primary T Cells: Induction of Promoter Activation in CD95LP-Luc Transgenic Mice. J. Immunol.
164: 4471-4480
[Abstract]
[Full Text]
-
Viret, C., Janeway, C. A. Jr.
(2000). Functional and Phenotypic Evidence for Presentation of E{alpha}52-68 Structurally Related Self-Peptide(s) in I-E{alpha}-Deficient Mice. J. Immunol.
164: 4627-4634
[Abstract]
[Full Text]
-
Bommhardt, U., Scheuring, Y., Bickel, C., Zamoyska, R., Hunig, T.
(2000). MEK Activity Regulates Negative Selection of Immature CD4+CD8+ Thymocytes. J. Immunol.
164: 2326-2337
[Abstract]
[Full Text]
-
Weiss, L., Whitmarsh, A. J., Yang, D. D., Rincon, M., Davis, R. J., Flavell, R. A.
(2000). Regulation of c-Jun NH2-terminal Kinase ( Jnk) Gene Expression during T Cell Activation. JEM
191: 139-146
[Abstract]
[Full Text]
-
Ludviksson, B. R., Ehrhardt, R. O., Strober, W.
(1999). Role of IL-12 in Intrathymic Negative Selection. J. Immunol.
163: 4349-4359
[Abstract]
[Full Text]
-
Freedman, B. D., Liu, Q.-H., Somersan, S., Kotlikoff, M. I., Punt, J. A.
(1999). Receptor Avidity and Costimulation Specify the Intracellular Ca2+ Signaling Pattern in Cd4+Cd8+ Thymocytes. JEM
190: 943-952
[Abstract]
[Full Text]
-
Page, D. M.
(1999). Cutting Edge: Thymic Selection and Autoreactivity Are Regulated by Multiple Coreceptors Involved in T Cell Activation. J. Immunol.
163: 3577-3581
[Abstract]
[Full Text]
-
Kishimoto, H., Sprent, J.
(1999). Strong TCR Ligation Without Costimulation Causes Rapid Onset of Fas-Dependent Apoptosis of Naive Murine CD4+ T Cells. J. Immunol.
163: 1817-1826
[Abstract]
[Full Text]
-
Baldwin, K. K., Trenchak, B. P., Altman, J. D., Davis3, M. M.
(1999). Negative Selection of T Cells Occurs Throughout Thymic Development. J. Immunol.
163: 689-698
[Abstract]
[Full Text]
-
Kishimoto, H., Sprent, J.
(1999). Several Different Cell Surface Molecules Control Negative Selection of Medullary Thymocytes. JEM
190: 65-74
[Abstract]
[Full Text]
-
Chiarle, R., Podda, A., Prolla, G., Podack, E. R., Thorbecke, G. J., Inghirami, G.
(1999). CD30 Overexpression Enhances Negative Selection in the Thymus and Mediates Programmed Cell Death Via a Bcl-2-Sensitive Pathway. J. Immunol.
163: 194-205
[Abstract]
[Full Text]
-
Moulian, N., Renvoize, C., Desodt, C., Serraf, A., Berrih-Aknin, S.
(1999). Functional Fas Expression in Human Thymic Epithelial Cells. Blood
93: 2660-2670
[Abstract]
[Full Text]
-
Manning, T. C., Parke, E. A., Teyton, L., Kranz, D. M.
(1999). Effects of Complementarity Determining Region Mutations on the Affinity of an {alpha}/{beta} T Cell Receptor: Measuring the Energy Associated with CD4/CD8 Repertoire Skewing. JEM
189: 461-470
[Abstract]
[Full Text]
-
McGargill, M. A., Hogquist, K. A.
(1999). Antigen-Induced Coreceptor Down-Regulation on Thymocytes Is Not a Result of Apoptosis. J. Immunol.
162: 1237-1245
[Abstract]
[Full Text]
-
Dautigny, N., Le Campion, A., Lucas, B.
(1999). Timing and Casting for Actors of Thymic Negative Selection. J. Immunol.
162: 1294-1302
[Abstract]
[Full Text]
-
Amsen, D., Calvo, C. R., Osborne, B. A., Kruisbeek, A. M.
(1999). Costimulatory signals are required for induction of transcription factor Nur77 during negative selection of CD4+CD8+ thymocytes. Proc. Natl. Acad. Sci. USA
96: 622-627
[Abstract]
[Full Text]
-
Anderson, M., Hernandez-Hoyos, G, Diamond, R., Rothenberg, E.
(1999). Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage. Development
126: 3131-3148
[Abstract]
-
ZHANG, J., DEYOUNG, A., KASLER, H.G., KABRA, N.H., KUANG, A.A., DIEHL, G., SOHN, S.J., BISHOP, C., WINOTO, A.
(1999). Receptor-mediated Apoptosis in T Lymphocytes. Cold Spring Harb Symp Quant Biol
64: 363-372
[Abstract]
-
Fatenejad, S., Peng, S. L., Disorbo, O., Craft, J.
(1998). Central T Cell Tolerance in Lupus-Prone Mice: Influence of Autoimmune Background and the lpr Mutation. J. Immunol.
161: 6427-6432
[Abstract]
[Full Text]
-
Rincon, M., Whitmarsh, A., Yang, D. D., Weiss, L., Derijard, B., Jayaraj, P., Davis, R. J., Flavell, R. A.
(1998). The JNK Pathway Regulates the In Vivo Deletion of Immature CD4+CD8+ Thymocytes. JEM
188: 1817-1830
[Abstract]
[Full Text]
-
Cilio, C. M., Daws, M. R., Malashicheva, A., Sentman, C. L., Holmberg, D.
(1998). Cytotoxic T Lymphocyte Antigen 4 Is Induced in the Thymus upon In Vivo Activation and Its Blockade Prevents Anti-CD3-mediated Depletion of Thymocytes. JEM
188: 1239-1246
[Abstract]
[Full Text]
-
Kench, J. A., Russell, D. M., Nemazee, D.
(1998). Efficient Peripheral Clonal Elimination of B Lymphocytes in MRL/lpr Mice Bearing Autoantibody Transgenes. JEM
188: 909-917
[Abstract]
[Full Text]
-
Moulian, N., Bidault, J., Planche, C., Berrih-Aknin, S.
(1998). Two Signaling Pathways Can Increase Fas Expression in Human Thymocytes. Blood
92: 1297-1307
[Abstract]
[Full Text]
-
Kishimoto, H., Surh, C. D., Sprent, J.
(1998). A Role for Fas in Negative Selection of Thymocytes In Vivo. JEM
187: 1427-1438
[Abstract]
[Full Text]
-
Fleck, M., Zhou, T., Tatsuta, T., Yang, P., Wang, Z., Mountz, J. D.
(1998). Fas/Fas Ligand Signaling During Gestational T Cell Development. J. Immunol.
160: 3766-3775
[Abstract]
[Full Text]
-
Van Parijs, L., Biuckians, A., Abbas, A. K.
(1998). Functional Roles of Fas and Bcl-2-Regulated Apoptosis of T Lymphocytes. J. Immunol.
160: 2065-2071
[Abstract]
[Full Text]
-
Page, D. M., Roberts, E. M., Peschon, J. J., Hedrick, S. M.
(1998). TNF Receptor-Deficient Mice Reveal Striking Differences Between Several Models of Thymocyte Negative Selection. J. Immunol.
160: 120-133
[Abstract]
[Full Text]
-
Punt, J. A., Havran, W., Abe, R., Sarin, A., Singer, A.
(1997). 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. JEM
186: 1911-1922
[Abstract]
[Full Text]
-
Wong, B., Arron, J., Choi, Y.
(1997). T Cell Receptor Signals Enhance Susceptibility to Fas-mediated Apoptosis. JEM
186: 1939-1944
[Abstract]
[Full Text]
-
Alam, A., Braun, M. Y., Hartgers, F., Lesage, S., Cohen, L., Hugo, P., Denis, F., Sekaly, R.-P.
(1997). Specific Activation of the Cysteine Protease CPP32 during the Negative Selection of T Cells in the Thymus. JEM
186: 1503-1512
[Abstract]
[Full Text]