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. 1998 Jul 15;102(2):421–429. doi: 10.1172/JCI3205

Defective expression of p56lck in an infant with severe combined immunodeficiency.

F D Goldman 1, Z K Ballas 1, B C Schutte 1, J Kemp 1, C Hollenback 1, N Noraz 1, N Taylor 1
PMCID: PMC508901  PMID: 9664084

Abstract

Severe combined immune deficiency (SCID) is a heterogeneous disorder characterized by profound defects in cellular and humoral immunity. We report here an infant with clinical and laboratory features of SCID and selective CD4 lymphopenia and lack of CD28 expression on CD8(+) T cells. T cells from this patient showed poor blastogenic responses to various mitogens and IL-2. Other T cell antigen receptor- induced responses, including upregulation of CD69, were similarly inhibited. However, more proximal T cell antigen receptor signaling events, such as anti-CD3 induced protein tyrosine phosphorylation, phosphorylation of mitogen-associated protein kinase, and calcium mobilization were intact. Although p59fyn and ZAP-70 protein tyrosine kinases were expressed at normal levels, a marked decrease in the level of p56lck was noted. Furthermore, this decrease was associated with the presence of an alternatively spliced lck transcript lacking the exon 7 kinase encoding domain. These data suggest that a deficiency in p56lck expression can produce a SCID phenotype in humans.

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Selected References

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  1. Appleby M. W., Gross J. A., Cooke M. P., Levin S. D., Qian X., Perlmutter R. M. Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn. Cell. 1992 Sep 4;70(5):751–763. doi: 10.1016/0092-8674(92)90309-z. [DOI] [PubMed] [Google Scholar]
  2. Arnaiz-Villena A., Timon M., Corell A., Perez-Aciego P., Martin-Villa J. M., Regueiro J. R. Brief report: primary immunodeficiency caused by mutations in the gene encoding the CD3-gamma subunit of the T-lymphocyte receptor. N Engl J Med. 1992 Aug 20;327(8):529–533. doi: 10.1056/NEJM199208203270805. [DOI] [PubMed] [Google Scholar]
  3. Arpaia E., Shahar M., Dadi H., Cohen A., Roifman C. M. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. Cell. 1994 Mar 11;76(5):947–958. doi: 10.1016/0092-8674(94)90368-9. [DOI] [PubMed] [Google Scholar]
  4. Ballas Z. K., Turner J. M., Turner D. A., Goetzman E. A., Kemp J. D. A patient with simultaneous absence of "classical" natural killer cells (CD3-, CD16+, and NKH1+) and expansion of CD3+, CD4-, CD8-, NKH1+ subset. J Allergy Clin Immunol. 1990 Feb;85(2):453–459. doi: 10.1016/0091-6749(90)90155-w. [DOI] [PubMed] [Google Scholar]
  5. Chan A. C., Kadlecek T. A., Elder M. E., Filipovich A. H., Kuo W. L., Iwashima M., Parslow T. G., Weiss A. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science. 1994 Jun 10;264(5165):1599–1601. doi: 10.1126/science.8202713. [DOI] [PubMed] [Google Scholar]
  6. Chu D. H., Spits H., Peyron J. F., Rowley R. B., Bolen J. B., Weiss A. The Syk protein tyrosine kinase can function independently of CD45 or Lck in T cell antigen receptor signaling. EMBO J. 1996 Nov 15;15(22):6251–6261. [PMC free article] [PubMed] [Google Scholar]
  7. D'Ambrosio D., Cantrell D. A., Frati L., Santoni A., Testi R. Involvement of p21ras activation in T cell CD69 expression. Eur J Immunol. 1994 Mar;24(3):616–620. doi: 10.1002/eji.1830240319. [DOI] [PubMed] [Google Scholar]
  8. Elder M. E., Lin D., Clever J., Chan A. C., Hope T. J., Weiss A., Parslow T. G. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science. 1994 Jun 10;264(5165):1596–1599. doi: 10.1126/science.8202712. [DOI] [PubMed] [Google Scholar]
  9. Goldsmith M. A., Weiss A. Isolation and characterization of a T-lymphocyte somatic mutant with altered signal transduction by the antigen receptor. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6879–6883. doi: 10.1073/pnas.84.19.6879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Groves T., Smiley P., Cooke M. P., Forbush K., Perlmutter R. M., Guidos C. J. Fyn can partially substitute for Lck in T lymphocyte development. Immunity. 1996 Nov;5(5):417–428. doi: 10.1016/s1074-7613(00)80498-7. [DOI] [PubMed] [Google Scholar]
  11. Hara T., Jung L. K., Bjorndahl J. M., Fu S. M. Human T cell activation. III. Rapid induction of a phosphorylated 28 kD/32 kD disulfide-linked early activation antigen (EA 1) by 12-o-tetradecanoyl phorbol-13-acetate, mitogens, and antigens. J Exp Med. 1986 Dec 1;164(6):1988–2005. doi: 10.1084/jem.164.6.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hurley T. R., Luo K., Sefton B. M. Activators of protein kinase C induce dissociation of CD4, but not CD8, from p56lck. Science. 1989 Jul 28;245(4916):407–409. doi: 10.1126/science.2787934. [DOI] [PubMed] [Google Scholar]
  13. Jennings C., Rich K., Siegel J. N., Landay A. A phenotypic study of CD8+ lymphocyte subsets in infants using three-color flow cytometry. Clin Immunol Immunopathol. 1994 Apr;71(1):8–13. doi: 10.1006/clin.1994.1044. [DOI] [PubMed] [Google Scholar]
  14. June C. H., Fletcher M. C., Ledbetter J. A., Samelson L. E. Increases in tyrosine phosphorylation are detectable before phospholipase C activation after T cell receptor stimulation. J Immunol. 1990 Mar 1;144(5):1591–1599. [PubMed] [Google Scholar]
  15. Kawai K., Kishihara K., Molina T. J., Wallace V. A., Mak T. W., Ohashi P. S. Impaired development of V gamma 3 dendritic epidermal T cells in p56lck protein tyrosine kinase-deficient and CD45 protein tyrosine phosphatase-deficient mice. J Exp Med. 1995 Jan 1;181(1):345–349. doi: 10.1084/jem.181.1.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Laurence J., Mitra D., Steiner M., Lynch D. H., Siegal F. P., Staiano-Coico L. Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia. J Clin Invest. 1996 Feb 1;97(3):672–680. doi: 10.1172/JCI118464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Levin S. D., Anderson S. J., Forbush K. A., Perlmutter R. M. A dominant-negative transgene defines a role for p56lck in thymopoiesis. EMBO J. 1993 Apr;12(4):1671–1680. doi: 10.1002/j.1460-2075.1993.tb05812.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ley S. C., Marsh M., Bebbington C. R., Proudfoot K., Jordan P. Distinct intracellular localization of Lck and Fyn protein tyrosine kinases in human T lymphocytes. J Cell Biol. 1994 May;125(3):639–649. doi: 10.1083/jcb.125.3.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Macchi P., Villa A., Giliani S., Sacco M. G., Frattini A., Porta F., Ugazio A. G., Johnston J. A., Candotti F., O'Shea J. J. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995 Sep 7;377(6544):65–68. doi: 10.1038/377065a0. [DOI] [PubMed] [Google Scholar]
  20. McCloskey T. W., Cavaliere T., Bakshi S., Harper R., Fagin J., Kohn N., Pahwa S. Immunophenotyping of T lymphocytes by three-color flow cytometry in healthy newborns, children, and adults. Clin Immunol Immunopathol. 1997 Jul;84(1):46–55. doi: 10.1006/clin.1997.4370. [DOI] [PubMed] [Google Scholar]
  21. Molina T. J., Kishihara K., Siderovski D. P., van Ewijk W., Narendran A., Timms E., Wakeham A., Paige C. J., Hartmann K. U., Veillette A. Profound block in thymocyte development in mice lacking p56lck. Nature. 1992 May 14;357(6374):161–164. doi: 10.1038/357161a0. [DOI] [PubMed] [Google Scholar]
  22. Mombaerts P., Anderson S. J., Perlmutter R. M., Mak T. W., Tonegawa S. An activated lck transgene promotes thymocyte development in RAG-1 mutant mice. Immunity. 1994 Jul;1(4):261–267. doi: 10.1016/1074-7613(94)90077-9. [DOI] [PubMed] [Google Scholar]
  23. Negishi I., Motoyama N., Nakayama K., Nakayama K., Senju S., Hatakeyama S., Zhang Q., Chan A. C., Loh D. Y. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature. 1995 Aug 3;376(6539):435–438. doi: 10.1038/376435a0. [DOI] [PubMed] [Google Scholar]
  24. Penninger J., Kishihara K., Molina T., Wallace V. A., Timms E., Hedrick S. M., Mak T. W. Requirement for tyrosine kinase p56lck for thymic development of transgenic gamma delta T cells. Science. 1993 Apr 16;260(5106):358–361. doi: 10.1126/science.8469988. [DOI] [PubMed] [Google Scholar]
  25. Perlmutter R. M., Marth J. D., Lewis D. B., Peet R., Ziegler S. F., Wilson C. B. Structure and expression of lck transcripts in human lymphoid cells. J Cell Biochem. 1988 Oct;38(2):117–126. doi: 10.1002/jcb.240380206. [DOI] [PubMed] [Google Scholar]
  26. Rabinovitch P. S., June C. H., Grossmann A., Ledbetter J. A. Heterogeneity among T cells in intracellular free calcium responses after mitogen stimulation with PHA or anti-CD3. Simultaneous use of indo-1 and immunofluorescence with flow cytometry. J Immunol. 1986 Aug 1;137(3):952–961. [PubMed] [Google Scholar]
  27. Ransom J. T., Chen M., Sandoval V. M., Pasternak J. A., Digiusto D., Cambier J. C. Increased plasma membrane permeability to Ca2+ in anti-Ig-stimulated B lymphocytes is dependent on activation of phosphoinositide hydrolysis. J Immunol. 1988 May 1;140(9):3150–3155. [PubMed] [Google Scholar]
  28. Russell S. M., Tayebi N., Nakajima H., Riedy M. C., Roberts J. L., Aman M. J., Migone T. S., Noguchi M., Markert M. L., Buckley R. H. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science. 1995 Nov 3;270(5237):797–800. doi: 10.1126/science.270.5237.797. [DOI] [PubMed] [Google Scholar]
  29. Samelson L. E., Patel M. D., Weissman A. M., Harford J. B., Klausner R. D. Antigen activation of murine T cells induces tyrosine phosphorylation of a polypeptide associated with the T cell antigen receptor. Cell. 1986 Sep 26;46(7):1083–1090. doi: 10.1016/0092-8674(86)90708-7. [DOI] [PubMed] [Google Scholar]
  30. Saukkonen J. J., Kornfeld H., Berman J. S. Expansion of a CD8+CD28- cell population in the blood and lung of HIV-positive patients. J Acquir Immune Defic Syndr. 1993 Nov;6(11):1194–1204. [PubMed] [Google Scholar]
  31. Schmidt D., Goronzy J. J., Weyand C. M. CD4+ CD7- CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest. 1996 May 1;97(9):2027–2037. doi: 10.1172/JCI118638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sefton B. M., Taddie J. A. Role of tyrosine kinases in lymphocyte activation. Curr Opin Immunol. 1994 Jun;6(3):372–379. doi: 10.1016/0952-7915(94)90115-5. [DOI] [PubMed] [Google Scholar]
  33. Shahinian A., Pfeffer K., Lee K. P., Kündig T. M., Kishihara K., Wakeham A., Kawai K., Ohashi P. S., Thompson C. B., Mak T. W. Differential T cell costimulatory requirements in CD28-deficient mice. Science. 1993 Jul 30;261(5121):609–612. doi: 10.1126/science.7688139. [DOI] [PubMed] [Google Scholar]
  34. Shaw A. S., Amrein K. E., Hammond C., Stern D. F., Sefton B. M., Rose J. K. The lck tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino-terminal domain. Cell. 1989 Nov 17;59(4):627–636. doi: 10.1016/0092-8674(89)90008-1. [DOI] [PubMed] [Google Scholar]
  35. Sleasman J. W., Tedder T. F., Barrett D. J. Combined immunodeficiency due to the selective absence of CD4 inducer T lymphocytes. Clin Immunol Immunopathol. 1990 Jun;55(3):401–417. doi: 10.1016/0090-1229(90)90127-c. [DOI] [PubMed] [Google Scholar]
  36. Stein P. L., Lee H. M., Rich S., Soriano P. pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell. 1992 Sep 4;70(5):741–750. doi: 10.1016/0092-8674(92)90308-y. [DOI] [PubMed] [Google Scholar]
  37. Straus D. B., Weiss A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell. 1992 Aug 21;70(4):585–593. doi: 10.1016/0092-8674(92)90428-f. [DOI] [PubMed] [Google Scholar]
  38. Taniguchi T., Miyazaki T., Minami Y., Kawahara A., Fujii H., Nakagawa Y., Hatakeyama M., Liu Z. J. IL-2 signaling involves recruitment and activation of multiple protein tyrosine kinases by the IL-2 receptor. Ann N Y Acad Sci. 1995 Sep 7;766:235–244. doi: 10.1111/j.1749-6632.1995.tb26671.x. [DOI] [PubMed] [Google Scholar]
  39. Testi R., Phillips J. H., Lanier L. L. T cell activation via Leu-23 (CD69). J Immunol. 1989 Aug 15;143(4):1123–1128. [PubMed] [Google Scholar]
  40. Thoenes G., Soudais C., le Deist F., Griscelli C., Fischer A., Lisowska-Grospierre B. Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient. J Biol Chem. 1992 Jan 5;267(1):487–493. [PubMed] [Google Scholar]
  41. Turner J. M., Brodsky M. H., Irving B. A., Levin S. D., Perlmutter R. M., Littman D. R. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell. 1990 Mar 9;60(5):755–765. doi: 10.1016/0092-8674(90)90090-2. [DOI] [PubMed] [Google Scholar]
  42. Veillette A., Horak I. D., Horak E. M., Bookman M. A., Bolen J. B. Alterations of the lymphocyte-specific protein tyrosine kinase (p56lck) during T-cell activation. Mol Cell Biol. 1988 Oct;8(10):4353–4361. doi: 10.1128/mcb.8.10.4353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Weinberg K., Parkman R. Severe combined immunodeficiency due to a specific defect in the production of interleukin-2. N Engl J Med. 1990 Jun 14;322(24):1718–1723. doi: 10.1056/NEJM199006143222406. [DOI] [PubMed] [Google Scholar]
  44. Weiss A. T cell antigen receptor signal transduction: a tale of tails and cytoplasmic protein-tyrosine kinases. Cell. 1993 Apr 23;73(2):209–212. doi: 10.1016/0092-8674(93)90221-b. [DOI] [PubMed] [Google Scholar]
  45. Wiest D. L., Ashe J. M., Howcroft T. K., Lee H. M., Kemper D. M., Negishi I., Singer D. S., Singer A., Abe R. A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development. Immunity. 1997 Jun;6(6):663–671. doi: 10.1016/s1074-7613(00)80442-2. [DOI] [PubMed] [Google Scholar]
  46. Wu G., Danska J. S., Guidos C. J. Lck dependence of signaling pathways activated by gamma-irradiation and CD3 epsilon engagement in RAG-1(-/-)-immature thymocytes. Int Immunol. 1996 Jul;8(7):1159–1164. doi: 10.1093/intimm/8.7.1159. [DOI] [PubMed] [Google Scholar]
  47. van Oers N. S., Lowin-Kropf B., Finlay D., Connolly K., Weiss A. alpha beta T cell development is abolished in mice lacking both Lck and Fyn protein tyrosine kinases. Immunity. 1996 Nov;5(5):429–436. doi: 10.1016/s1074-7613(00)80499-9. [DOI] [PubMed] [Google Scholar]

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