Abstract
The activation of a T cell through T cell receptor (TCR) is fundamental to adaptive immune responses. The lymphocyte specific kinase (LCK) plays a central role in the initiation of signaling from the TCR. TCR activates LCK through the adaptor protein uncoordinated 119 (UNC119). A mutation of human UNC119 impairs LCK activation and is associated with inadequate signaling, diminished T cell responses to TCR stimulation, CD4 lymphopenia, and infections of viral, bacterial, and fungal origin. The above clinical and immunological findings meet the criteria of the idiopathic CD4 lymphopenia (ICL). The discovery of the UNC119 defect provides a molecular mechanism for a subset of patients with this previously unexplained disease. Here we review our recent findings on the UNC119 mutation in ICL.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of outstanding importance
Walker UA, Warnatz K. Idiopathic CD4 lymphocytopenia. Curr Opin Rheumatol. 2006;18:389–95.
Smith DK, Neal JJ, Holmberg SD. Unexplained opportunistic infections and CD4+ T-lymphocytopenia without HIV infection. An investigation of cases in the United States. The Centers for Disease Control Idiopathic CD4+ T-lymphocytopenia Task Force. N Engl J Med. 1993;328:373–9.
•• Gorska MM, Alam R. A mutation in the human Uncoordinated 119 gene impairs TCR signaling and is associated with CD4 lymphopenia. Blood. 2012;119:1399–406. This is our original report on the UNC119 mutation in ICL..
•• Kuijpers TW, Ijspeert H, van Leeuwen EM, et al. Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations. Blood. 2011;117:5892–6. This paper describes the RAG1 mutation in ICL..
•• Li FY, Chaigne-Delalande B, Kanellopoulou C, et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature. 2011;475:471–6. This paper characterizes MAGT1 mutations in ICL/XMEN..
Zonios DI, Falloon J, Bennett JE, et al. Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors. Blood. 2008;112:287–94.
Duncan RA, von Reyn CF, Alliegro GM, et al. Idiopathic CD4+ T-lymphocytopenia-4 patients with opportunistic infections and no evidence of HIV infection. N Engl J Med. 1993;328:393–8.
Spira TJ, Jones BM, Nicholson JK, et al. Idiopathic CD4+ T-lymphocytopenia–an analysis of 5 patients with unexplained opportunistic infections. N Engl J Med. 1993;328:386–92.
Netea MG, Brouwer AE, Hoogendoorn EH, et al. Two patients with cryptococcal meningitis and idiopathic CD4 lymphopenia: defective cytokine production and reversal by recombinant interferon- gamma therapy. Clin Infect Dis. 2004;39:e83–7.
Laurence J, Mitra D, Steiner M, et al. Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia. J Clin Invest. 1996;97:672–80.
Scott-Algara D, Balabanian K, Chakrabarti LA, et al. Idiopathic CD4+ T-cell lymphocytopenia is associated with impaired membrane expression of the chemokine receptor CXCR4. Blood. 2010;115:3708–17.
Isgrò A, Sirianni MC, Gramiccioni C, et al. Idiopathic CD4+ lymphocytopenia may be due to decreased bone marrow clonogenic capability. Int Arch Allergy Immunol. 2005;136:379–84.
Puronen CE, Thompson WL, Imamichi H, et al. Decreased interleukin 7 responsiveness of T lymphocytes in patients with idiopathic CD4 lymphopenia. J Infect Dis. 2012;205:1382–90.
Hubert P, Bergeron F, Ferreira V, et al. Defective p56Lck activity in T cells from an adult patient with idiopathic CD4+ lymphocytopenia. Int Immunol. 2000;12:449–57.
Straus DB, Weiss A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell. 1992;70:585–93.
• Salmond RJ, Filby A, Qureshi I, et al. T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunol Rev. 2009;228:9–22. Excellent review on SRC family tyrosine kinases in T cells..
Molina TJ, Kishihara K, Siderovski DP, et al. Profound block in thymocyte development in mice lacking p56lck. Nature. 1992;357:161–4.
Goldman FD, Ballas ZK, Schutte BC, et al. Defective expression of p56lck in an infant with severe combined immunodeficiency. J Clin Invest. 1998;102:421–9.
Sawabe T, Horiuchi T, Nakamura M, et al. Defect of lck in a patient with common variable immunodeficiency. Int J Mol Med. 2001;7:609–14.
Cen O, Gorska MM, Stafford SJ, et al. Identification of UNC119 as a novel activator of SRC-type tyrosine kinases. J Biol Chem. 2003;278:8837–45.
Gorska MM, Stafford SJ, Cen O, et al. Unc119, a novel activator of Lck/Fyn, is essential for T cell activation. J Exp Med. 2004;199:369–79.
Gorska MM, Liang Q, Karim Z, Alam R. Uncoordinated 119 protein controls trafficking of Lck via the Rab11 endosome and is critical for immunological synapse formation. J Immunol. 2009;183:1675–84.
Gorska MM, Goplen N, Liang Q, Alam R. Uncoordinated 119 preferentially induces Th2 differentiation and promotes the development of asthma. J Immunol. 2010;184:4488–96.
Sicheri F, Moarefi I, Kuriyan J. Crystal structure of the Src family tyrosine kinase Hck. Nature. 1997;385:602–9.
Xu W, Harrison SC, Eck MJ. Three-dimensional structure of the tyrosine kinase c-Src. Nature. 1997;385:595–602.
Mustelin T, Altman A. Dephosphorylation and activation of the T cell tyrosine kinase pp 56lck by the leukocyte common antigen (CD45). Oncogene. 1990;5:809–13.
Cahir McFarland ED, Hurley TR, Pingel JT, et al. Correlation between Src family member regulation by the protein-tyrosine-phosphatase CD45 and transmembrane signaling through the T-cell receptor. Proc Natl Acad Sci USA. 1993;90:1402–6.
Moarefi I, LaFevre-Bernt M, Sicheri F, et al. Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement. Nature. 1997;385:650–3.
Kobayashi A, Higashide T, Hamasaki D, et al. HRG4 (UNC119) mutation found in cone-rod dystrophy causes retinal degeneration in a transgenic model. Invest Ophthalmol Vis Sci. 2000;41:3268–77.
Kubota S, Kobayashi A, Mori N, et al. Changes inretinal synaptic proteins in the transgenic model expressing a mutant HRG4(UNC119). Invest Ophthalmol Vis Sci. 2002;43:308–13.
Niehues T, Perez-Becker R, Schuetz C. More than just SCID–the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135:183–92.
Sobacchi C, Marrella V, Rucci F, et al. RAG-dependent primary immunodeficiencies. Hum Mutat. 2006;27:1174–84.
Acknowledgments
This work was supported by NIH grants R01 AI0059719 and PPG HL36577 to R.A. and M.M.G., and by the Sheldon C. Siegel - Asthma and Allergy Foundation of America (AAFA) Investigator Award Grant, the Colorado Clinical and Translational Sciences Institute (CCTSI) Junior Faculty Pilot Award (NIH/NCRR Colorado CTSI UL1 RR025780), and the CCTSI KL2 Research Scholar Award (NIH/NCRR Colorado CTSI KL2 RR025779) to MMG.
Disclosure
No potential conflicts of interest relevant to this article were reported.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gorska, M.M., Alam, R. Consequences of a Mutation in the UNC119 Gene for T Cell Function in Idiopathic CD4 Lymphopenia. Curr Allergy Asthma Rep 12, 396–401 (2012). https://doi.org/10.1007/s11882-012-0281-4
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11882-012-0281-4