Coreceptor Signal Strength Regulates Positive Selection but Does Not Determine CD4/CD8 Lineage Choice in a Physiologic In Vivo Model

Erman, Batu; Alag, Amala; Dahle, Øyvind; Laethem, François Van; Sarafova, Sophia D.; Guinter, Terry I.; Sharrow, Susan O.; Grinberg, Alexander; Love, Paul E.; Singer, Alfred

doi:10.4049/jimmunol.177.10.6613

Cited by 30 publications

(41 citation statements)

References 50 publications

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“…The studies presented here support this idea and reveal two key elements regarding the role SLP-76 plays during thymocyte selection. First, globally reduced SLP-76 expression in the T cell compartment has a more pronounced effect on generation of CD4 SP thymocytes, consistent with the notion that positive selection of MHC class II-restricted thymocytes is normally more efficient than MHC class I-restricted thymocytes as a result of the more robust nature of CD4 coreceptor signaling when compared with CD8 [19]. Second, a substantial portion of HY TCR ϩ thymocytes escapes the early deletion, normally observed in male mice, when SLP-76 expression is governed solely by Tg-mediated reconstitution, highlighting the importance of maintaining SLP-76 expression from the endogenous loci to the selection process.…”

Section: Discussionsupporting

confidence: 66%

“…This is thought to result in a stronger or more sustained signal, which supports efficient positive selection. The weaker signals associated with CD8 coreceptor engagement are also sufficient to support positive selection, albeit with less efficiency than CD4-associated signaling [19]. The low levels of SLP-76 expression achieved in Line 2 SLP-76Ϫ/Ϫ Tg ϩ mice are predicted to depress signaling potential in the DP thymocyte compartment, an idea supported by our observation that reduced surface expression of CD5 on DP thymocytes correlates with reduced SLP-76 expression.…”

Section: Discussionsupporting

confidence: 59%

“…It is therefore difficult to envision how reduced signaling potential would enhance positive selection of MHC class I-restricted thymocytes and generation of CD8 SP thymocytes, resulting in the skewed CD4: CD8 ratio observed in Tg-reconstituted SLP-76Ϫ/Ϫ mice derived from Line 2 Tg founders. It remains possible that reduced SLP-76 expression could affect the outcome of lineage commitment, especially if sustained signaling via CD4 coreceptor engagement is required to fully commit selected thymocytes to the CD4 lineage [19]. Compromised signaling potential as a consequence of reduced SLP-76 expression may mimic the developmental cues that normally promote adoption of a CD8 SP fate, resulting in redirection of MHC class II-restricted thymocytes into the CD8 lineage.…”

Section: Discussionmentioning

confidence: 99%

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Impaired thymic selection in mice expressing altered levels of the SLP-76 adaptor protein

Ramsey

Luckashenak

Koretzky

et al. 2007

Journal of Leukocyte Biology

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Intracellular signaling initiated by ligation of the TCR influences cell fate at multiple points during the lifespan of a T cell. This is especially evident during thymic selection, where the nature of TCR-dependent signaling helps to establish a MHC-restricted, self-tolerant T cell repertoire. The Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76) adaptor protein is a required intermediate in multiple signaling pathways triggered by TCR engagement, several of which have been implicated in dictating the outcome of thymic selection (e.g., intracellular calcium flux and activation of ERK family MAPKs). To determine if thymocyte maturation and selection at later stages of development are sensitive to perturbations in SLP-76 levels, we analyzed these crucial events using several transgenic (Tg) lines of mice expressing altered levels of SLP-76 in the thymus. In Tg mice expressing low levels of SLP-76 in preselection thymocytes, the CD4:CD8 ratio in the thymus and spleen was skewed in a manner consistent with impaired selection and/or maturation of CD4+ thymocytes. Low SLP-76 expression also correlated with reduced CD5 expression on immature thymocytes, consistent with reduced TCR signaling potential. In contrast, reconstitution of SLP-76 at higher levels resulted in normal thymic CD5 expression and CD4:CD8 ratios in the thymus and periphery. It is curious that thymic deletion of TCR-Tg (HY) thymocytes was markedly impaired in both lines of Tg-reconstituted SLP-76-/- mice. Studies using chimeric mice indicate that the defect in deletion of HY+ thymocytes is intrinsic to the developing thymocyte, suggesting that maintenance of sufficient SLP-76 expression from the endogenous locus is a key element in the selection process.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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Impaired thymic selection in mice expressing altered levels of the SLP-76 adaptor protein

Ramsey

Luckashenak

Koretzky

et al. 2007

Journal of Leukocyte Biology

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“…CD8.4 OT-I Rag2 −/− β2m −/− strain was generated by crossing CD8.4 knock-in mouse (Erman et al, 2006) with OT-I Rag2 −/− β2m −/− . Mice were bred in our colony (University Hospital Basel) in accordance with Cantonal and Federal laws of Switzerland.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, coreceptors are vitally important for selecting T cells that recognize pMHCI and pMHCII antigens (Van Laethem et al, 2013). Along these lines, increasing Lck coupling to CD8 enhances the efficiency of positive selection of MHCI-restricted thymocytes (Erman et al, 2006). …”

Section: Introductionmentioning

confidence: 99%

Coreceptor Scanning by the T Cell Receptor Provides a Mechanism for T Cell Tolerance

Štěpánek

Prabhakar

Osswald

et al. 2014

Cell

149

255

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Summary In the thymus, high affinity, self-reactive thymocytes are eliminated from the pool of developing T cells, generating central tolerance. Here, we investigate how developing T cells measure self-antigen affinity. We show that very few CD4 or CD8 coreceptor molecules are coupled with the signal-initiating kinase, Lck. To initiate signaling, an antigen engaged T cell receptor (TCR) scans multiple coreceptor molecules to find one that is coupled to Lck. Coreceptor scanning is the first and rate-limiting step in a kinetic proofreading chain of events that eventually leads to TCR triggering and negative selection. MHCII-restricted TCRs require a shorter antigen dwell time (~0.2s) to initiate negative selection compared to MHCI restricted TCRs (~0.9s) because more CD4 coreceptors are Lck-loaded compared to CD8. Based on experimental data and mathematical analysis, we generated a model (Lck come&stay/signal duration) that accurately predicts the experimentally observed differences in antigen dwell-time thresholds used by MHCI- and MHCII-restricted thymocytes to initiate negative selection and generate self-tolerance.

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Lipid‐mediated presentation of MHC class II molecules guides thymocytes to the CD4 lineage

et al. 2009

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Previous studies on the MHC class-specific differentiation of CD4 + CD8 + thymocytes into CD4 + and CD8 + T cells have focused on the role of coreceptor molecules. However, CD4 and CD8 T cells develop according to their MHC class specificities even in these mice lacking coreceptors. This study investigated the possibility that lineage is determined not only by coreceptors, but is also guided by the way how MHC molecules are presented. MHC class II molecules possess a highly conserved Cys in their transmembrane domain, which is palmitoylated and thereby associates with lipid rafts, whereas neither palmitoylation nor raft association was observed with MHC class I molecules. The generation of CD4 T cells was impaired and that of CD8 T cells was augmented when the rafts on the thymic epithelial cells were disrupted. This was due to the conversion of MHC class II-specific thymocytes from the CD4 lineage to CD8. The ability of I-A d molecule to associate with rafts was lost when its transmembrane Cys was replaced. The development of DO11.10 thymocytes recognizing this mutant I-A dm was converted from CD4 to CD8. These results suggest that the CD4 lineage commitment is directed by the raft-associated presentation of MHC class II molecules.Key words: CD4 T cell . Lipid rafts . MHC class II molecule . Thymic selection Supporting Information available online IntroductionThe ab T cells differentiate from immature CD4 + CD8 + doublepositive (DP) thymocytes to mature CD4 + and CD8 + singlepositive (SP) T cells in the thymus. This differentiation is achieved through TCR signaling that follows the engagement with self-MHC peptide complexes. The resulting CD4 and CD8 T cells possess MHC class II-specific TCR and MHC class I-specific TCR, respectively, which is consistent with MHC binding specificities of the coreceptors they express. The exact mechanism by which the DP thymocytes are committed to the appropriate T-cell lineage is not yet clear.Earlier investigations on CD4 versus CD8 lineage commitment in the thymus have focused on the roles played by coreceptor molecules. Robey et al. [1] proposed the presence of an instructive signal for CD8 T-cell development and demonstrated that constitutive CD8 expression induces substantial increase in the CD8 lineage commitment, while it has no apparent effect on CD4 96lineage commitment. The instructive model is supported for CD4 T-cell development as well, by experiments in which transgenic chimeric molecules consisting of the CD8a extracellular domain and transmembrane (TM) of CD4 or CD8 and the cytoplasmic domain of CD4 were shown to induce CD4 T cells expressing MHC class I-specific TCR [2,3]. The identification of a defect that impairs only CD4 T-cell development also supports the instructive model [4]. These observations collectively suggest that the coreceptors instruct thymocytes to differentiate into either CD4 or CD8 T cells by initiating qualitatively distinct signals. However, the functional differences between the CD4 and CD8 are mostly quantitative, i.e. more Lck molecu...

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Coreceptor Signal Strength Regulates Positive Selection but Does Not Determine CD4/CD8 Lineage Choice in a Physiologic In Vivo Model

Cited by 30 publications

References 50 publications

Impaired thymic selection in mice expressing altered levels of the SLP-76 adaptor protein

Impaired thymic selection in mice expressing altered levels of the SLP-76 adaptor protein

Coreceptor Scanning by the T Cell Receptor Provides a Mechanism for T Cell Tolerance

Lipid‐mediated presentation of MHC class II molecules guides thymocytes to the CD4 lineage

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