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Unraveling a Revealing Paradox: Why Major Histocompatibility Complex I

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Unraveling a Revealing Paradox: Why Major Histocompatibility Complex I Unraveling a Revealing Paradox: Why Major Histocompatibility Complex I–signaled Thymocytes “Paradoxically” Appear as CD4ϩ8lo Transitional Cells During Positive Selection of CD8 T Cells Remy Bosselut,1 Terry I. Guinter,2 Susan O. Sharrow,2 and Alfred Singer2 1Laboratory of Immune Cell Biology and 2Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Abstract The mechanism by which T cell receptor specificity determines the outcome of the CD4/CD8 lineage decision in the thymus is not known. An important clue is the fact that major histocom- patibility complex (MHC)-I–signaled thymocytes paradoxically appear as CD4ϩ8lo transitional cells during their differentiation into CD8 T cells. Lineage commitment is generally thought to occur at the CD4ϩ8 (double positive) stage of differentiation and to result in silencing of the opposite coreceptor gene. From this perspective, the appearance of MHC-I–signaled thy- mocytes as CD4ϩ8lo cells would be due to effects on CD8 surface protein expression, not CD8 gene expression. But contrary to this perspective, this study demonstrates that MHC-I–signaled thymocytes appear as CD4ϩ8lo cells because of transient down-regulation of CD8 gene ex- pression, not because of changes in CD8 surface protein expression or distribution. This study also demonstrates that initial cessation of CD8 gene expression in MHC-I–signaled thymocytes is not necessarily indicative of commitment to the CD4 T cell lineage, as such thymocytes re- tain the potential to differentiate into CD8 T cells. These results challenge classical concepts of lineage commitment but fulfill predictions of the kinetic signaling model. Key words: lineage commitment • kinetic signaling • coreceptor reversal • positive selection Introduction Immature CD4ϩ8 (double positive [DP]*) thymocytes are TCR engagement of peptide–MHC-II complexes generally signaled in the thymus to differentiate into mature single requires coengagement of surface CD4 coreceptor molecules positive T cells by TCR engagement of intrathymic whereas TCR engagement of peptide–MHC-I complexes The Journal of Experimental Medicine MHC–peptide complexes (1). TCR engagement of in- generally requires coengagement of surface CD8 corecep- trathymic peptide–MHC-II complexes results in differenti- tor molecules (4, 5). However, the actual mechanism by ation of DP thymocytes into mature CD4 T cells whereas which TCR and coreceptor coengagements influence lin- TCR engagement of intrathymic peptide–MHC-I com- eage choice remains a matter of intense controversy. plexes results in differentiation of DP thymocytes into Classical models of lineage commitment are of two gen- mature CD8 T cells (2, 3). The mechanism by which the eral types: instructional and stochastic (6–10). Instructional MHC class specificity of surface TCR complexes deter- models of lineage commitment propose that TCR plus mines lineage choice remains an unresolved problem in CD4 coengagements on DP thymocytes terminate CD8 developmental immunology. It is thought that lineage gene expression and dictate commitment to the CD4 T choice is a consequence of the coreceptor molecules that cell lineage by transducing signals that differ either qualita- individual TCRs use to engage intrathymic ligands, as tively or quantitatively (in strength or duration) from sig- nals transduced by TCR plus CD8 coengagements that terminate CD4 gene expression and dictate commitment to Address correspondence to Alfred Singer, Experimental Immunology the CD8 T cell lineage (11–15). Stochastic models of lin- Branch, National Cancer Institute, Building 10, Room 4B36, Be- thesda, MD 20892. Phone: 301-496-5461; Fax: 301-496-0887; E-mail: eage commitment propose that coengagement of TCR [email protected] with either coreceptor molecule signals DP thymocytes to *Abbreviations used in this paper: DP, double positive; hCD2, human CD2. randomly terminate expression of one coreceptor gene, 1709 The Journal of Experimental Medicine • Volume 197, Number 12, June 16, 2003 1709–1719 http://www.jem.org/cgi/doi/10.1084/jem.20030170 with only thymocytes still expressing matching TCR and expression on MHC-I–signaled thymocytes during CD8 T coreceptor molecules responsive to subsequent survival sig- cell differentiation tests predictions made by different con- nals (16, 17). In both models, lineage commitment is pos- cepts of how lineage commitment occurs. The classical con- tulated to occur in DP thymocytes and result in silencing of cept that lineage commitment occurs in DP thymocytes and the opposite coreceptor gene. results in irreversible silencing of the opposite coreceptor As a result, classical models of lineage commitment pre- gene predicts that low CD8 surface protein expression on dict that DP thymocytes that have committed to the CD4ϩ MHC-I–signaled CD4ϩ8lo thymocytes is due to direct ef- T cell lineage have terminated CD8 gene expression and fects on CD8 surface protein expression, not CD8 gene ex- therefore will lose CD8 surface protein expression and ap- pression. In contrast, the kinetic signaling model predicts pear as CD4ϩ8lo transitional cells. Reciprocally, signaled that low CD8 surface protein expression on MHC-I–sig- DP thymocytes that have committed to the CD8 T cell naled CD4ϩ8lo thymocytes is due to down-regulation of lineage have terminated CD4 gene expression and will lose CD8 gene expression. Consequently, this study has at- CD4 surface protein expression and appear as CD4lo8ϩ tempted to determine the actual basis for reduced CD8 sur- cells. However, experimental observations are discordant face protein expression on MHC-I–signaled CD4ϩ8lo thy- with these predictions as assessment of CD4ϩ8lo and mocytes. These results demonstrate that reduced CD8 CD4lo8 transitional populations revealed that a significant surface expression on MHC-I–signaled CD4ϩ8lo thymocytes proportion of CD8 lineage cells initially appear as CD4ϩ8lo is not due to internalization nor slow reexpression of CD8 transitional cells (18–22). The appearance of CD8-commit- surface proteins, but is due to down-regulated CD8 gene ted thymocytes as CD4ϩ8lo transitional cells is paradoxical expression. In addition, this study demonstrates that down- on two levels, as: (a) CD8-committed thymocytes are regulation of CD8 gene expression does not imply commit- thought to have terminated CD4 gene expression, yet these ment to the CD4 lineage, as many intermediate CD4ϩ8Ϫ cells display high levels of CD4 proteins on their cell sur- thymocytes retain the ability to differentiate into CD8 T face, and (b) CD8-committed thymocytes are thought to cells. These results support the kinetic signaling model but express CD8 coreceptor genes, yet these cells display low challenge more classical concepts of lineage commitment. levels of CD8 proteins on their cell surface. Although the paradoxical loss of CD8 surface proteins on MHC-I–sig- naled thymocytes had not been predicted, it could be rec- Materials and Methods onciled with classical lineage commitment models by hy- Animals. Mice deficient in MHC-II (MHC-IIo; reference pothesizing that it was due to a direct effect of MHC-I 27), CD8 (CD8␣o; reference 5), or CD8 (CD8␤o; reference signals on CD8 surface proteins that resulted in reduced 28) were used at 8–12 wk of age and maintained in our own ani- mal facility. MHC-IIo mice were bred with CD8␣o mice to gen- CD8 expression on CD8-committed thymocytes (9, 22, o o erate IIЊCD8␣ mice, and were bred with CD8␤ mice to gener- 23). This classical view of CD8 T cell differentiation is de- ate IIЊCD8␤o mice. picted in Fig. 1 A. CD8 transgenic mice constructed with human CD2 (hCD2)- In contrast, the kinetic signaling model of lineage com- based CD8 transgenes encoding either full-length CD8 or tail- mitment proposes that signaled DP thymocytes terminate less CD8 molecules have been described (29, 30). Transgenic CD8 gene expression and transcriptionally convert into and endogenous CD8 proteins expressed different allelic forms CD4ϩ8 intermediate thymocytes that still retain the po- of CD8 with transgenic CD8 proteins being CD8␣.1 and en- tential to differentiate into either CD4 or CD8 T cells dogenous CD8␣ proteins being CD8␣.2. The CD8 transgenic (24–26). So kinetic signaling postulates that lineage com- mouse lines expressed transgenic and endogenous CD8 proteins at comparable levels. The CD8␣.1 transgene was introduced by mitment occurs after DP thymocytes have converted into The Journal of Experimental Medicine o o ␣o o ␤ CD4ϩ8 intermediate thymocytes. According to the ki- mating into MHC-II , II CD8 , and II CD8 mice to generate MHC-IIo mice that either expressed both endogenous and netic signaling model, lineage direction is determined in ␣ ϩ transgenic CD8 proteins or expressed only transgenic CD8 CD4 8 intermediate thymocytes simply by whether proteins. TCR-mediated positive selection signals persist or cease. If ϩ Line 30 transgenic mice expressing a transgene encoding TCR signaling persists, intermediate CD4 8 thymocytes hCD2 cDNA under the control of the CD4 locus control region differentiate into CD4 T cells, but if TCR signaling (including the CD4 silencer element) were provided by D. Litt- ceases, intermediate CD4ϩ8 thymocytes differentiate into man (Skirball Institute of Biomolecular Medicine, New York, CD8 T cells. As a result, a critical step in the differentia- NY; 31). Surface expression of hCD2 protein on thymocytes and tion of intermediate CD4ϩ8 thymocytes into CD8 T T cells in Line 30 mice serves as a faithful reporter
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