Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice (original) (raw)

• Chong, M. M. et al. Suppressor of cytokine signaling-1 is a critical regulator of interleukin-7-dependent CD8+ T cell differentiation. Immunity 18, 475–487 (2003).
  Article CAS PubMed Google Scholar
• Yu, Q. et al. Cytokine signal transduction is suppressed in preselection double-positive thymocytes and restored by positive selection. J. Exp. Med. 203, 165–175 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Doyle, C. & Strominger, J. L. Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature 330, 256–259 (1987).
  Article CAS PubMed Google Scholar
• Norment, A. M., Salter, R. D., Parham, P., Engelhard, V. H. & Littman, D. R. Cell–cell adhesion mediated by CD8 and MHC class I molecules. Nature 336, 79–81 (1988).
  Article CAS PubMed Google Scholar
• Shaw, A. S. et al. The lck tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino-terminal domain. Cell 59, 627–636 (1989).
  Article CAS PubMed Google Scholar
• Turner, J. M. et al. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell 60, 755–765 (1990).
  Article CAS PubMed Google Scholar
• Veillette, A., Bookman, M. A., Horak, E. M., Samelson, L. E. & Bolen, J. B. Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck. Nature 338, 257–259 (1989).
  Article CAS PubMed Google Scholar
• Veillette, A., Zuniga-Pflucker, J. C., Bolen, J. B. & Kruisbeek, A. M. Engagement of CD4 and CD8 expressed on immature thymocytes induces activation of intracellular tyrosine phosphorylation pathways. J. Exp. Med. 170, 1671–1680 (1989).
  Article CAS PubMed Google Scholar
• Teh, H. S. et al. Thymic major histocompatibility complex antigens and the αβ T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature 335, 229–233 (1988). This is the first report of a TCR-transgenic mouse and shows that CD4/CD8-lineage choice in the thymus is dictated by the MHC-restriction specificity of the positively selecting TCR.
  Article CAS PubMed Google Scholar
• Janeway, C. A. Jr. T-cell development. Accessories or coreceptors? Nature 335, 208–210 (1988).
  Article PubMed Google Scholar
• Chan, S. H., Cosgrove, D., Waltzinger, C., Benoist, C. & Mathis, D. Another view of the selective model of thymocyte selection. Cell 73, 225–236 (1993). This study provides support for the stochastic selection model by showing that MHC class II-deficient mice contain CD4+CD8 low thymocytes, which were thought to be MHC class I-restricted cells that were short-lived and that had randomly made an incorrect CD4-lineage choice.
  Article CAS PubMed Google Scholar
• Davis, C. B., Killeen, N., Crooks, M. E., Raulet, D. & Littman, D. R. Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell 73, 237–247 (1993). This study also provides support for the stochastic selection model through one of the first co-receptor rescue experiments in which constitutive expression of transgenic co-receptor proteins promoted the differentiation of positively selected thymocytes into mature T cells of the inappropriate lineage.
  Article CAS PubMed Google Scholar
• Itano, A., Kioussis, D. & Robey, E. Stochastic component to development of class I major histocompatibility complex-specific T cells. Proc. Natl Acad. Sci. USA 91, 220–224 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Leung, R. K. et al. Deletion of the CD4 silencer element supports a stochastic mechanism of thymocyte lineage commitment. Nature Immunol. 2, 1167–1173 (2001).
  Article CAS Google Scholar
• Robey, E., Itano, A., Fanslow, W. C. & Fowlkes, B. J. Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice. J. Exp. Med. 179, 1997–2004 (1994).
  Article CAS PubMed Google Scholar
• Chan, S. H., Waltzinger, C., Baron, A., Benoist, C. & Mathis, D. Role of coreceptors in positive selection and lineage commitment. Embo J. 13, 4482–4489 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Baron, A., Hafen, K. & von Boehmer, H. A human CD4 transgene rescues CD4-CD8+ cells in β2-microglobulin-deficient mice. Eur. J. Immunol. 24, 1933–1936 (1994).
  Article CAS PubMed Google Scholar
• Itano, A. & Robey, E. Highly efficient selection of CD4 and CD8 lineage thymocytes supports an instructive model of lineage commitment. Immunity 12, 383–389 (2000).
  Article CAS PubMed Google Scholar
• Keefe, R., Dave, V., Allman, D., Wiest, D. & Kappes, D. J. Regulation of lineage commitment distinct from positive selection. Science 286, 1149–1153 (1999). This study characterizes a spontaneously arising mutant mouse strain that lacks helper T cells (referred to as helper deficient mice) and provides the first evidence that positive selection and CD4/CD8-lineage choice are sequential, temporally distinct events.
  Article CAS PubMed Google Scholar
• Sarafova, S. D. et al. Modulation of coreceptor transcription during positive selection dictates lineage fate independently of TCR/coreceptor specificity. Immunity 23, 75–87 (2005). Using an elaborate in vivo model in which CD4 expression is regulated by Cd8 transcriptional control elements, this study shows that lineage commitment is determined by the kinetics of co-receptor transcription during positive selection signalling and not by the identity or signalling strength of the co-receptor proteins themselves.
  Article CAS PubMed Google Scholar
• Seong, R. H., Chamberlain, J. W. & Parnes, J. R. Signal for T-cell differentiation to a CD4 cell lineage is delivered by CD4 transmembrane region and/or cytoplasmic tail. Nature 356, 718–720 (1992).
  Article CAS PubMed Google Scholar
• Itano, A. et al. The cytoplasmic domain of CD4 promotes the development of CD4 lineage T cells. J. Exp. Med. 183, 731–741 (1996). This study proposes the strength-of-signal instructional model and provides the first experimental support for this model.
  Article CAS PubMed Google Scholar
• Wiest, D. L. et al. Regulation of T cell receptor expression in immature CD4+CD8+ thymocytes by p56lck tyrosine kinase: basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules. J. Exp. Med. 178, 1701–1712 (1993).
  Article CAS PubMed Google Scholar
• Hernandez-Hoyos, G., Sohn, S. J., Rothenberg, E. V. & Alberola-Ila, J. Lck activity controls CD4/CD8 T cell lineage commitment. Immunity 12, 313–322 (2000).
  Article CAS PubMed Google Scholar
• Sohn, S. J., Forbush, K. A., Pan, X. C. & Perlmutter, R. M. Activated p56lck directs maturation of both CD4 and CD8 single-positive thymocytes. J. Immunol. 166, 2209–2217 (2001).
  Article CAS PubMed Google Scholar
• Schmedt, C. & Tarakhovsky, A. Autonomous maturation of α/β T lineage cells in the absence of COOH-terminal Src kinase (Csk). J. Exp. Med. 193, 815–826 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Broussard, C. et al. Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. Immunity 25, 93–104 (2006).
  Article CAS PubMed Google Scholar
• Liao, X. C. & Littman, D. R. Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Immunity 3, 757–769 (1995).
  Article CAS PubMed Google Scholar
• Schaeffer, E. M. et al. Tec family kinases modulate thresholds for thymocyte development and selection. J. Exp. Med. 192, 987–1000 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Bommhardt, U., Basson, M. A., Krummrei, U. & Zamoyska, R. Activation of the extracellular signal-related kinase/mitogen-activated protein kinase pathway discriminates CD4 versus CD8 lineage commitment in the thymus. J. Immunol. 163, 715–722 (1999).
  CAS PubMed Google Scholar
• Fischer, A. M., Katayama, C. D., Pages, G., Pouyssegur, J. & Hedrick, S. M. The role of erk1 and erk2 in multiple stages of T cell development. Immunity 23, 431–443 (2005).
  Article CAS PubMed Google Scholar
• Sharp, L. L., Schwarz, D. A., Bott, C. M., Marshall, C. J. & Hedrick, S. M. The influence of the MAPK pathway on T cell lineage commitment. Immunity 7, 609–618 (1997).
  Article CAS PubMed Google Scholar
• Wilkinson, B. & Kaye, J. Requirement for sustained MAPK signaling in both CD4 and CD8 lineage commitment: a threshold model. Cell. Immunol. 211, 86–95 (2001).
  Article CAS PubMed Google Scholar
• Love, P. E., Lee, J. & Shores, E. W. Critical relationship between TCR signaling potential and TCR affinity during thymocyte selection. J. Immunol. 165, 3080–3087 (2000).
  Article CAS PubMed Google Scholar
• Holst, J. et al. Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nature Immunol. 9, 658–666 (2008).
  Article CAS Google Scholar
• Bosselut, R., Feigenbaum, L., Sharrow, S. O. & Singer, A. Strength of signaling by CD4 and CD8 coreceptor tails determines the number but not the lineage direction of positively selected thymocytes. Immunity 14, 483–494 (2001).
  Article CAS PubMed Google Scholar
• Erman, B. et al. Coreceptor signal strength regulates positive selection but does not determine CD4/CD8 lineage choice in a physiologic in vivo model. J. Immunol. 177, 6613–6625 (2006). This report uses gene knock-in technology to engineer the endogenous Cd8a gene so that it encodes stronger-signalling CD8–CD4 chimeric co-receptor proteins. It shows that the strength of co-receptor signalling does not alter CD4/CD8-lineage choice but instead has a quantitative effect on the number of DP thymocytes that are positively selected to differentiate into mature T cells.
  Article CAS PubMed Google Scholar
• Yasutomo, K., Doyle, C., Miele, L., Fuchs, C. & Germain, R. N. The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell lineage fate. Nature 404, 506–510 (2000).
  Article CAS PubMed Google Scholar
• Brugnera, E. et al. Coreceptor reversal in the thymus: signaled CD4+8+ thymocytes initially terminate CD8 transcription even when differentiating into CD8+ T cells. Immunity 13, 59–71 (2000). This is the original study that introduces the kinetic signalling model and describes results that contradict classical presumptions of CD4/CD8-lineage choice.
  Article CAS PubMed Google Scholar
• Singer, A. New perspectives on a developmental dilemma: the kinetic signaling model and the importance of signal duration for the CD4/CD8 lineage decision. Curr. Opin. Immunol. 14, 207–215 (2002).
  Article CAS PubMed Google Scholar
• Lundberg, K., Heath, W., Kontgen, F., Carbone, F. R. & Shortman, K. Intermediate steps in positive selection: differentiation of CD4+8int TCRint thymocytes into CD4−8+TCRhi thymocytes. J. Exp. Med. 181, 1643–1651 (1995).
  Article CAS PubMed Google Scholar
• Suzuki, H., Punt, J. A., Granger, L. G. & Singer, A. Asymmetric signaling requirements for thymocyte commitment to the CD4+ versus CD8+ T cell lineages: a new perspective on thymic commitment and selection. Immunity 2, 413–425 (1995). Published simultaneously with reference 41, these reports identify CD4+CD8 low thymocytes as precursors of both CD4+ and CD8+ T cells.
  Article CAS PubMed Google Scholar
• Aliahmad, P. & Kaye, J. Commitment issues: linking positive selection signals and lineage diversification in the thymus. Immunol. Rev. 209, 253–273 (2006).
  Article CAS PubMed Google Scholar
• Kappes, D. J., He, X. & He, X. CD4-CD8 lineage commitment: an inside view. Nature Immunol. 6, 761–766 (2005).
  Article CAS Google Scholar
• Kappes, D. J., He, X. & He, X. Role of the transcription factor Th-POK in CD4:CD8 lineage commitment. Immunol. Rev. 209, 237–252 (2006).
  Article CAS PubMed Google Scholar
• Lucas, B. & Germain, R. N. Unexpectedly complex regulation of CD4/CD8 coreceptor expression supports a revised model for CD4+CD8+ thymocyte differentiation. Immunity 5, 461–477 (1996).
  Article CAS PubMed Google Scholar
• He, X. et al. CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus. Immunity 28, 346–358 (2008).
  Article CAS PubMed Google Scholar
• Bosselut, R., Guinter, T. I., Sharrow, S. O. & Singer, A. Unraveling a revealing paradox: why major histocompatibility complex I-signaled thymocytes “paradoxically” appear as CD4+8lo transitional cells during positive selection of CD8+ T cells. J. Exp. Med. 197, 1709–1719 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Barthlott, T., Kohler, H. & Eichmann, K. Asynchronous coreceptor downregulation after positive thymic selection: prolonged maintenance of the double positive state in CD8 lineage differentiation due to sustained biosynthesis of the CD4 coreceptor. J. Exp. Med. 185, 357–362 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Singer, A. & Bosselut, R. CD4/CD8 coreceptors in thymocyte development, selection, and lineage commitment: analysis of the CD4/CD8 lineage decision. Adv. Immunol. 83, 91–131 (2004).
  Article CAS PubMed Google Scholar
• Yu, Q., Erman, B., Bhandoola, A., Sharrow, S. O. & Singer, A. In vitro evidence that cytokine receptor signals are required for differentiation of double positive thymocytes into functionally mature CD8+ T cells. J. Exp. Med. 197, 475–487 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Noguchi, M. et al. Functional cleavage of the common cytokine receptor γ chain (γc) by calpain. Proc. Natl Acad. Sci. USA 94, 11534–11539 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Park, J. H. et al. 'Coreceptor tuning': cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nature Immunol. 8, 1049–1059 (2007).
  Article CAS Google Scholar
• Rathmell, J. C., Vander Heiden, M. G., Harris, M. H., Frauwirth, K. A. & Thompson, C. B. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol. Cell 6, 683–692 (2000).
  Article CAS PubMed Google Scholar
• Wofford, J. A., Wieman, H. L., Jacobs, S. R., Zhao, Y. & Rathmell, J. C. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 111, 2101–2111 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Catlett, I. M. & Hedrick, S. M. Suppressor of cytokine signaling 1 is required for the differentiation of CD4+ T cells. Nature Immunol. 6, 715–721 (2005).
  Article CAS Google Scholar
• Yucel, R., Karsunky, H., Klein-Hitpass, L. & Moroy, T. The transcriptional repressor Gfi1 affects development of early, uncommitted c-Kit+ T cell progenitors and CD4/CD8 lineage decision in the thymus. J. Exp. Med. 197, 831–844 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Ellmeier, W., Sawada, S. & Littman, D. R. The regulation of CD4 and CD8 coreceptor gene expression during T cell development. Annu. Rev. Immunol. 17, 523–554 (1999).
  Article CAS PubMed Google Scholar
• Kioussis, D. & Ellmeier, W. Chromatin and CD4, CD8α and CD8β gene expression during thymic differentiation. Nature Rev. Immunol. 2, 909–919 (2002).
  Article CAS Google Scholar
• Sawada, S., Scarborough, J. D., Killeen, N. & Littman, D. R. A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development. Cell 77, 917–929 (1994).
  Article CAS PubMed Google Scholar
• Siu, G., Wurster, A. L., Duncan, D. D., Soliman, T. M. & Hedrick, S. M. A transcriptional silencer controls the developmental expression of the CD4 gene. EMBO J. 13, 3570–3579 (1994). Together with reference 60, this report describes the identification of a Cd4 silencer element that transcriptionally suppresses CD4 expression in CD4 − thymocytes.
  Article CAS PubMed PubMed Central Google Scholar
• Ellmeier, W., Sunshine, M. J., Losos, K. & Littman, D. R. Multiple developmental stage-specific enhancers regulate CD8 expression in developing thymocytes and in thymus-independent T cells. Immunity 9, 485–496 (1998).
  Article CAS PubMed Google Scholar
• Hostert, A. et al. Hierarchical interactions of control elements determine CD8α gene expression in subsets of thymocytes and peripheral T cells. Immunity 9, 497–508 (1998). Together with reference 62, this report identifies individual enhancer elements that are responsible for the developmental and stage-specific transcription of the Cd8a gene during T-cell development.
  Article CAS PubMed Google Scholar
• Ellmeier, W., Sunshine, M. J., Losos, K., Hatam, F. & Littman, D. R. An enhancer that directs lineage-specific expression of CD8 in positively selected thymocytes and mature T cells. Immunity 7, 537–547 (1997).
  Article CAS PubMed Google Scholar
• Hostert, A. et al. A CD8 genomic fragment that directs subset-specific expression of CD8 in transgenic mice. J. Immunol. 158, 4270–4281 (1997).
  CAS PubMed Google Scholar
• Feik, N. et al. Functional and molecular analysis of the double-positive stage-specific CD8 enhancer E8III during thymocyte development. J. Immunol. 174, 1513–24 (2005).
  Article CAS PubMed Google Scholar
• Hostert, A. et al. A region in the CD8 gene locus that directs expression to the mature CD8 T cell subset in transgenic mice. Immunity 7, 525–536 (1997).
  Article CAS PubMed Google Scholar
• Yao, Z. et al. Stat5a/b are essential for normal lymphoid development and differentiation. Proc. Natl Acad. Sci. USA 103, 1000–1005 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, X. & Bosselut, R. Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo. Nature Immunol. 5, 280–288 (2004).
  Article CAS Google Scholar
• Kadlecek, T. A. et al. Differential requirements for ZAP-70 in TCR signaling and T cell development. J. Immunol. 161, 4688–4694 (1998).
  CAS PubMed Google Scholar
• Liu, X. et al. Restricting Zap70 expression to CD4+CD8+ thymocytes reveals a T cell receptor-dependent proofreading mechanism controlling the completion of positive selection. J. Exp. Med. 197, 363–373 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Negishi, I. et al. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435–438 (1995).
  Article CAS PubMed Google Scholar
• Harker, N. et al. The CD8α gene locus is regulated by the Ikaros family of proteins. Mol. Cell 10, 1403–1415 (2002).
  Article CAS PubMed Google Scholar
• Urban, J. A. & Winandy, S. Ikaros null mice display defects in T cell selection and CD4 versus CD8 lineage decisions. J. Immunol. 173, 4470–4478 (2004).
  Article CAS PubMed Google Scholar
• Naito, T., Gomez- Del Arco, P., Williams, C. J. & Georgopoulos, K. Antagonistic interactions between Ikaros and the chromatin remodeler Mi-2β determine silencer activity and Cd4 gene expression. Immunity 27, 723–734 (2007).
  Article CAS PubMed Google Scholar
• Williams, C. J. et al. The chromatin remodeler Mi-2β is required for CD4 expression and T cell development. Immunity 20, 719–733 (2004).
  Article CAS PubMed Google Scholar
• Chi, T. H. et al. Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes. Nature 418, 195–199 (2002).
  Article CAS PubMed Google Scholar
• Aliahmad, P. & Kaye, J. Development of all CD4 T lineages requires nuclear factor TOX. J. Exp. Med. 205, 245–256 (2008). This study documents that, in the absence of the HMG box protein TOX, the development of CD4-lineage T cells is blocked, thereby identifying TOX as one of the nuclear factors that are required for CD4-lineage choice.
  Article CAS PubMed PubMed Central Google Scholar
• Bosselut, R. CD4/CD8-lineage differentiation in the thymus: from nuclear effectors to membrane signals. Nature Rev. Immunol. 4, 529–540 (2004).
  Article CAS Google Scholar
• Egawa, T., Tillman, R. E., Naoe, Y., Taniuchi, I. & Littman, D. R. The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. J. Exp. Med. 204, 1945–1957 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• He, X. et al. The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 433, 826–833 (2005). This study uses positional cloning to identify a point mutation in Th-POK as being responsible for the absence of CD4+ T cells in HD mice. Reciprocally, transgene-encoded Th-POK proteins are shown to redirect the differentiation of MHC class I-selected thymocytes into CD4+ T cells.
  Article CAS PubMed Google Scholar
• Hernandez-Hoyos, G., Anderson, M. K., Wang, C., Rothenberg, E. V. & Alberola-Ila, J. GATA-3 expression is controlled by TCR signals and regulates CD4/CD8 differentiation. Immunity 19, 83–94 (2003).
  Article CAS PubMed Google Scholar
• Sato, T. et al. Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes. Immunity 22, 317–328 (2005).
  Article CAS PubMed Google Scholar
• Setoguchi, R. et al. Repression of the transcription factor Th-POK by Runx complexes in cytotoxic T cell development. Science 319, 822–825 (2008).
  Article CAS PubMed Google Scholar
• Sun, G. et al. The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nature Immunol. 6, 373–381 (2005). Together with reference 81, this study identifies Th-POK as a CD4-lineage-determining factor and as the putative CD4-lineage master gene.
  Article CAS Google Scholar
• Taniuchi, I., Ellmeier, W. & Littman, D. R. The CD4/CD8 lineage choice: new insights into epigenetic regulation during T cell development. Adv. Immunol. 83, 55–89 (2004).
  Article CAS PubMed Google Scholar
• Grueter, B. et al. Runx3 regulates integrin αE/CD103 and CD4 expression during development of CD4−/CD8+ T cells. J. Immunol. 175, 1694–1705 (2005).
  Article CAS PubMed Google Scholar
• Aliahmad, P. et al. TOX provides a link between calcineurin activation and CD8 lineage commitment. J. Exp. Med. 199, 1089–1099 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Wilkinson, B. et al. TOX: an HMG box protein implicated in the regulation of thymocyte selection. Nature Immunol. 3, 272–280 (2002).
  Article CAS Google Scholar
• Hendriks, R. W. et al. Expression of the transcription factor GATA-3 is required for the development of the earliest T cell progenitors and correlates with stages of cellular proliferation in the thymus. Eur. J. Immunol. 29, 1912–1918 (1999).
  Article CAS PubMed Google Scholar
• Nawijn, M. C. et al. Enforced expression of GATA-3 during T cell development inhibits maturation of CD8 single-positive cells and induces thymic lymphoma in transgenic mice. J. Immunol. 167, 715–723 (2001).
  Article CAS PubMed Google Scholar
• Galera, P., Musso, M., Ducy, P. & Karsenty, G. c-Krox, a transcriptional regulator of type I collagen gene expression, is preferentially expressed in skin. Proc. Natl Acad. Sci. USA 91, 9372–9376 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Dave, V. P., Allman, D., Keefe, R., Hardy, R. R. & Kappes, D. J. HD mice: a novel mouse mutant with a specific defect in the generation of CD4+ T cells. Proc. Natl Acad. Sci. USA 95, 8187–8192 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Jenkinson, S. R. et al. Expression of the transcription factor cKrox in peripheral CD8 T cells reveals substantial postthymic plasticity in CD4-CD8 lineage differentiation. J. Exp. Med. 204, 267–272 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Taniuchi, I. et al. Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111, 621–633 (2002). This report identifies RUNX-family transcription factors as crucial mediators of Cd4 gene repression.
  Article CAS PubMed Google Scholar
• Levanon, D. & Groner, Y. Structure and regulated expression of mammalian RUNX genes. Oncogene 23, 4211–4219 (2004).
  Article CAS PubMed Google Scholar
• Woolf, E. et al. Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis. Proc. Natl Acad. Sci. USA 100, 7731–7736 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kohu, K. et al. Overexpression of the Runx3 transcription factor increases the proportion of mature thymocytes of the CD8 single-positive lineage. J. Immunol. 174, 2627–2636 (2005).
  Article CAS PubMed Google Scholar
• Liu, X., Taylor, B. J., Sun, G. & Bosselut, R. Analyzing expression of perforin, Runx3, and Thpok genes during positive selection reveals activation of CD8-differentiation programs by MHC II-signaled thymocytes. J. Immunol. 175, 4465–4474 (2005).
  Article CAS PubMed Google Scholar
• Schilham, M. W. & Clevers, H. HMG box containing transcription factors in lymphocyte differentiation. Semin. Immunol. 10, 127–132 (1998).
  Article CAS PubMed Google Scholar
• Stros, M., Launholt, D. & Grasser, K. D. The HMG-box: a versatile protein domain occurring in a wide variety of DNA-binding proteins. Cell. Mol. Life Sci. 64, 2590–2606 (2007).
  Article CAS PubMed Google Scholar
• Hedrick, S. M. Thymus lineage commitment: a single switch. Immunity 28, 297–299 (2008).
  Article CAS PubMed Google Scholar
• Pai, S. Y. et al. Critical roles for transcription factor GATA-3 in thymocyte development. Immunity 19, 863–875 (2003).
  Article CAS PubMed Google Scholar
• Huseby, E. S. et al. How the T cell repertoire becomes peptide and MHC specific. Cell 122, 247–260 (2005).
  Article CAS PubMed Google Scholar
• Zerrahn, J., Held, W. & Raulet, D. H. The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88, 627–636 (1997).
  Article CAS PubMed Google Scholar
• Van Laethem, F. et al. Deletion of CD4 and CD8 coreceptors permits generation of αβT cells that recognize antigens independently of the MHC. Immunity 27, 735–750 (2007). This study shows that TCRs that engage non-MHC ligands in the thymus cannot access co-receptor associated LCK and so cannot transduce intracellular signals that would rescue thymocytes from death by neglect.
  Article CAS PubMed Google Scholar
• Wiest, D. L., Ashe, J. M., Abe, R., Bolen, J. B. & Singer, A. TCR activation of ZAP70 is impaired in CD4+CD8+ thymocytes as a consequence of intrathymic interactions that diminish available p56lck. Immunity 4, 495–504 (1996).
  Article CAS PubMed Google Scholar
• Haughn, L. et al. Association of tyrosine kinase p56lck with CD4 inhibits the induction of growth through the αβ T-cell receptor. Nature 358, 328–331 (1992).
  Article CAS PubMed Google Scholar
• Yu, M. et al. Nucleoprotein structure of the CD4 locus: implications for the mechanisms underlying CD4 regulation during T cell development. Proc. Natl Acad. Sci. USA 105, 3873–3878 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Bilic, I. et al. Negative regulation of CD8 expression via Cd8 enhancer-mediated recruitment of the zinc finger protein MAZR. Nature Immunol. 7, 392–400 (2006).
  Article CAS Google Scholar
• Adlam, M., Duncan, D. D., Ng, D. K. & Siu, G. Positive selection induces CD4 promoter and enhancer function. Int. Immunol. 9, 877–887 (1997).
  Article CAS PubMed Google Scholar
• Uematsu, Y., Donda, A. & De Libero, G. Thymocytes control the CD4 gene differently from mature T lymphocytes. Int. Immunol. 9, 179–187 (1997).
  Article CAS PubMed Google Scholar
• Wurster, A. L., Siu, G., Leiden, J. M. & Hedrick, S. M. Elf-1 binds to a critical element in a second CD4 enhancer. Mol. Cell Biol. 14, 6452–6463 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Zou, Y. R. et al. Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage. Nature Genet. 29, 332–336 (2001).
  Article CAS PubMed Google Scholar
• Allen, R. D. 3rd, Kim, H. K., Sarafova, S. D. & Siu, G. Negative regulation of CD4 gene expression by a HES-1-c-Myb complex. Mol. Cell. Biol. 21, 3071–3082 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, H. K. & Siu, G. The notch pathway intermediate HES-1 silences CD4 gene expression. Mol. Cell. Biol. 18, 7166–7175 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Wildt, K. F. et al. The transcription factor Zbtb7b promotes CD4 expression by antagonizing Runx-mediated activation of the CD4 silencer. J. Immunol. 179, 4405–4414 (2007).
  Article CAS PubMed Google Scholar