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CD4 and CD8 Single-Positive Thymocytes Directs Maturation Of Activated p56lck Directs Maturation of Both CD4 and CD8 Single-Positive Thymocytes Sue J. Sohn, Katherine A. Forbush, Xiao Cun Pan and Roger M. Perlmutter This information is current as of October 1, 2021. J Immunol 2001; 166:2209-2217; ; doi: 10.4049/jimmunol.166.4.2209 http://www.jimmunol.org/content/166/4/2209 Downloaded from References This article cites 57 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/166/4/2209.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Activated p56lck Directs Maturation of Both CD4 and CD8 Single-Positive Thymocytes1 Sue J. Sohn,2* Katherine A. Forbush,* Xiao Cun Pan,* and Roger M. Perlmutter† p56lck is a protein tyrosine kinase expressed throughout T cell development. It associates noncovalently with the cytoplasmic domains of the CD4 and CD8 coreceptor molecules and has been implicated in TCR signaling in mature T cells. Its role in early thymocyte differentiation has been demonstrated in vivo, both by targeted gene disruption and by transgene expression. Previ- ously, we showed that expression of a dominant-negative form of p56lck in double-positive thymocytes inhibits positive selection. We now demonstrate that expression of constitutively activated p56lck (p56lckF505) accelerates the transition from the double- positive to the single-positive stage. Importantly, p56lckF505 drives survival and lineage commitment of thymocytes in the absence of TCR engagement by appropriate MHC molecules. These results indicate that activation of p56lck constitutes an early step in conveying maturational signals after TCR ligation by a positively selecting ligand. Our study provides direct in vivo evidence for the role of p56lck in regulating TCR signaling. The Journal of Immunology, 2001, 166: 2209–2217. Downloaded from aturation of thymocytes from CD4ϩCD8ϩ double- in Ref. 15). For example, constitutive expression of the CD8 mol- positive (DP)3 to CD4ϩ or CD8ϩ single-positive (SP) ecule permits maturation of CD4ϩ helper T cells (CD4ϩCD8Tgϩ) stage requires signals generated by the concerted in- bearing an MHC class I-restricted TCR (16, 17). Conversely, con- M ϩ teraction of surface TCRs and CD4 or CD8 coreceptors and the stitutive expression of CD4 molecules rescues CD8 cytotoxic T appropriate MHC molecule (reviewed in Refs. 1 and 2). DP thy- cells bearing a class II-specific TCR (18). Thus, thymocytes ex- http://www.jimmunol.org/ mocytes that interact with self-MHC with sufficient affinity survive pressing class I-restricted TCRs were shown to be positively se- and proceed through final maturation steps (positive selection). T lected in the absence of CD8 when cultured with peptide variants cells that fail to interact or that bind MHC molecules too strongly that artificially improved TCR-MHC interactions (19, 20). These undergo apoptosis (death by neglect and negative selection, re- studies indicate that manipulations that change interactions among spectively) (reviewed in Ref. 2). The transition from the DP to SP the TCR, coreceptor, and MHC invoke differential intracellular ϩ stage is also accompanied by commitment to either the CD4 signals to direct T cell maturation. ϩ helper or CD8 cytotoxic T cell lineage, a decision influenced by Following the TCR ␣ (␣) chain gene rearrangement, the DP the Ag specificity of the TCR and the appropriate MHC-coreceptor thymocytes undergoing selection express clonotypic ␣- and the match. For example, transgenic mice constitutively expressing ␤-polypeptide chains which comprise a structure that can bind the by guest on October 1, 2021 MHC class I-restricted TCRs or those expressing MHC class II- peptide/MHC complex. This heterodimeric receptor also associ- ϩ ϩ restricted TCRs possess mainly CD8 or CD4 T cells, respec- ates noncovalently with the invariant CD3 subunits and the ␨ tively (3–6). Conversely, mice deficient for MHC class I or class chains, which are required for transducing intracellular signals (21, ϩ ϩ II expression lack CD8 or CD4 T cells (7–10). Finally, mice 22). CD4 and CD8 coreceptors stabilize TCR-MHC interactions lacking CD4 or CD8 coreceptors possess greatly reduced numbers and enhance intracellular signaling events triggered by the TCR. of helper or cytotoxic lineage T cells (11–14). Thus, co-cross-linking CD4 and CD3 has been shown to enhance Although TCRs, coreceptors, and MHC molecules clearly direct the ability of T cells to flux Ca2ϩ relative to CD3 cross-linking the transition from the DP to SP stage, it is unlikely that a “correct” alone (23). In contrast, independent cross-linking of CD4 and CD3 combination of these components sends a strictly instructive signal decreased the Ca2ϩ response. These results indicate that corecep- which simultaneously dictates survival and lineage commitment. tors can contribute to the overall amplitude and/or quality of sig- Several studies support the notion that lineage commitment occurs nals transmitted by the TCR. Furthermore, expression of a chi- first and randomly but that survival depends on sustained, optimal meric coreceptor molecule containing the extracellular and coreceptor/TCR interactions with the MHC molecules (reviewed transmembrane domains of CD8␣ and the cytoplasmic domain of the CD4 molecule in F5 TCR (specific for a viral nucleoprotein b *Department of Immunology, University of Washington, Seattle, WA 98195; and peptide presented by H-2D ) transgenic mice promoted the matu- †Merck Research Laboratories, Rahway, NJ 07065 ration of CD4ϩ T cells expressing this class I-restricted TCR (24). Received for publication August 7, 2000. Accepted for publication November These results suggest that the cytoplasmic tail of the CD4 core- 15, 2000. ceptor can influence the outcome of the thymocyte cell fate The costs of publication of this article were defrayed in part by the payment of page decision. charges. This article must therefore be hereby marked advertisement in accordance lck with 18 U.S.C. Section 1734 solely to indicate this fact. The src family protein tyrosine kinase p56 is expressed 1 This work was supported in part by grants from the National Institutes of Health. mainly in T-lineage cells throughout T cell development (review in R.M.P. was an Investigator of the Howard Hughes Medical Institute. Ref. 25). It associates noncovalently with the cytoplasmic tails of 2 Address correspondence and reprint requests to Dr. Sue J. Sohn, Department of the CD4 and CD8 coreceptor molecules and becomes catalytically Molecular and Cell Biology, 465 LSA, University of California, Berkeley, CA 94720. activated when the coreceptors are cross-linked (26–30). Bio- E-mail address: [email protected] chemical evidence suggests that p56lck can also enhance signals 3 Abbreviations used in this paper: DP, double-positive; SP, single-positive; DN, double- ␤ ␤ mediated through the TCR/CD3 complex (31–33), although a di- negative; 2m, 2-microglobulin; HSA, heat-stable Ag; dLGF, distal promoter driving the lck gene bearing the F505 mutation; RAG, recombinase-activating gene. rect physical association between p56lck and TCR/CD3 complex Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 2210 p56lck-DRIVEN MATURATION OF SP THYMOCYTES has not been established. More importantly, lack of functional AG-3Ј and the reverse primer sequence is 5Ј-CAG AGG GCA GAG GTG p56lck abrogated mature T cell activation in a mutant Jurkat sub- AGA CAG-3Ј. The absence of amplification product was scored as ho- clone (JCaM1), providing genetic evidence for the role of p56lck in mozygous disruption in each case. TCR signaling (34). In mice, targeted disruption of the lck gene, or Analyses of transgene expression by immunoblotting transgenic expression of catalytically inactive p56lck under the Transgene expression was determined by immunoblotting total lysates from control of the lck proximal promoter (which drives transgene ex- 5 Ϫ Ϫ thymocytes and splenocytes. Briefly, 5 ϫ 10 cells were lysed in buffer con- pression in the CD4 CD8 double-negative (DN) and DP thymo- taining 1% Triton X-100 (50 mM Tris (pH 7.5), 50 mM NaCl, 1 mM PMSF, cytes), interferes with both cellular expansion and allelic exclusion ␮ ␮ 1 g/ml aprotinin, 1 g/ml leupeptin, 1 mM Na3VO4), and the resulting ly- at the TCR ␤-chain gene locus during the transition from the DN sates were resolved in 10% SDS-PAGE, transferred onto nitrocellulose, blot- to the DP stage (35, 36). In addition, expression of an activated ted with affinity-purified anti-p56lck monoclonal reagent (3A5; Santa Cruz Bio- ␮ form of p56lck (p56lckF505) under the control of the lck proximal technology, Santa Cruz, CA) at 0.25 g/ml followed by incubation with HRP- conjugated sheep anti-mouse
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