CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson's disease
Jessica A Hutter Saunders, Katherine A Estes, Lisa M Kosloski, Heather E Allen, Kathryn M Dempsey, Diego R Torres-Russotto, Jane L Meza, Pamela M Santamaria, John M Bertoni, Daniel L Murman, Hesham H Ali, David G Standaert, R Lee Mosley, Howard E Gendelman, Jessica A Hutter Saunders, Katherine A Estes, Lisa M Kosloski, Heather E Allen, Kathryn M Dempsey, Diego R Torres-Russotto, Jane L Meza, Pamela M Santamaria, John M Bertoni, Daniel L Murman, Hesham H Ali, David G Standaert, R Lee Mosley, Howard E Gendelman
Abstract
Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson's disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified Parkinson's Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs.
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References
- Agace WW. Tissue-tropic effector T cells: generation and targeting opportunities. Nat Rev Immunol. 2006;6:682–692. doi: 10.1038/nri1869.
- Ashman LK, Aylett GW. Expression of CD31 epitopes on human lymphocytes: CD31 monoclonal antibodies differentiate between naive (CD45RA+) and memory (CD45RA-) CD4-positive T cells. Tissue Antigens. 1991;38:208–212. doi: 10.1111/j.1399-0039.1991.tb01899.x.
- Azevedo RI, Soares MV, Barata JT, Tendeiro R, Serra-Caetano A, Victorino RM, Sousa AE. IL-7 sustains CD31 expression in human naive CD4+ T cells and preferentially expands the CD31+ subset in a PI3K-dependent manner. Blood. 2009;113:2999–3007. doi: 10.1182/blood-2008-07-166223.
- Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord. 2005;11:493–498. doi: 10.1016/j.parkreldis.2005.07.005.
- Barker RA, Cahn AP. Parkinson’s disease: an autoimmune process. Int J Neurosci. 1988;43:1–7. doi: 10.3109/00207458808985773.
- Bas J, Calopa M, Mestre M, Mollevi DG, Cutillas B, Ambrosio S, Buendia E. Lymphocyte populations in Parkinson’s disease and in rat models of parkinsonism. J Neuroimmunol. 2001;113:146–152. doi: 10.1016/S0165-5728(00)00422-7.
- Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 2010;119:689–702. doi: 10.1007/s00401-010-0664-3.
- Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011;134:1293–1314. doi: 10.1093/brain/awr074.
- Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One. 2008;3:e1376. doi: 10.1371/journal.pone.0001376.
- Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 2009;119:182–192.
- Calopa M, Bas J, Callen A, Mestre M. Apoptosis of peripheral blood lymphocytes in Parkinson patients. Neurobiol Dis. 2010;38:1–7. doi: 10.1016/j.nbd.2009.12.017.
- Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I, Czlonkowski A. Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration. 1996;5:137–143. doi: 10.1006/neur.1996.0020.
- De Jong R, Brouwer M, Hooibrink B, Van der Pouw-Kraan T, Miedema F, Van Lier RA. The CD27- subset of peripheral blood memory CD4+ lymphocytes contains functionally differentiated T lymphocytes that develop by persistent antigenic stimulation in vivo. Eur J Immunol. 1992;22:993–999. doi: 10.1002/eji.1830220418.
- Demeure CE, Byun DG, Yang LP, Vezzio N, Delespesse G. CD31 (PECAM-1) is a differentiation antigen lost during human CD4 T-cell maturation into Th1 or Th2 effector cells. Immunology. 1996;88:110–115. doi: 10.1046/j.1365-2567.1996.d01-652.x.
- Denucci CC, Mitchell JS, Shimizu Y. Integrin function in T-cell homing to lymphoid and nonlymphoid sites: getting there and staying there. Crit Rev Immunol. 2009;29:87–109. doi: 10.1615/CritRevImmunol.v29.i2.10.
- Depper JM, Leonard WJ, Kronke M, Noguchi PD, Cunningham RE, Waldmann TA, Greene WC. Regulation of interleukin 2 receptor expression: effects of phorbol diester, phospholipase C, and reexposure to lectin or antigen. J Immunol. 1984;133:3054–3061.
- Di Sabatino A, Rovedatti L, Rosado MM, Carsetti R, Corazza GR, MacDonald TT. Increased expression of mucosal addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin alpha4beta7-positive T cells in blood. Hum Pathol. 2009;40:699–704. doi: 10.1016/j.humpath.2008.10.014.
- Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396:690–695. doi: 10.1038/25374.
- Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol. 2005;26:485–495. doi: 10.1016/j.it.2005.07.004.
- Fiszer U, Mix E, Fredrikson S, Kostulas V, Link H. Parkinson’s disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood. Acta Neurol Scand. 1994;90:160–166. doi: 10.1111/j.1600-0404.1994.tb02699.x.
- Fornasa G, Groyer E, Clement M, Dimitrov J, Compain C, Gaston AT, Varthaman A, Khallou-Laschet J, Newman DK, Graff-Dubois S, Nicoletti A, Caligiuri G. TCR stimulation drives cleavage and shedding of the ITIM receptor CD31. J Immunol. 2010;184:5485–5492. doi: 10.4049/jimmunol.0902219.
- Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes JD, Dodiya HB, Keshavarzian A. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One. 2011;6:e28032. doi: 10.1371/journal.pone.0028032.
- Gabay C. Interleukin-6 and chronic inflammation. Arthrit Res Ther. 2006;8(Suppl 2):S3. doi: 10.1186/ar1917.
- Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007;33:599–614. doi: 10.1111/j.1365-2990.2007.00874.x.
- Hendriks J, Xiao Y, Borst J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J Exp Med. 2003;198:1369–1380. doi: 10.1084/jem.20030916.
- Hintzen RQ, de Jong R, Lens SM, Brouwer M, Baars P, van Lier RA. Regulation of CD27 expression on subsets of mature T-lymphocytes. J Immunol. 1993;151:2426–2435.
- Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R (2007) How common are the “common” neurologic disorders? Neurology 68:326–337
- Hisanaga K, Asagi M, Itoyama Y, Iwasaki Y. Increase in peripheral CD4 bright +CD8 dull + T cells in Parkinson disease. Arch Neurol. 2001;58:1580–1583. doi: 10.1001/archneur.58.10.1580.
- Hoffman PM, Robbins DS, Nolte MT, Gibbs CJ, Jr, Gajdusek DC. Cellular immunity in Guamanians with amyotrophic lateral sclerosis and Parkinsonism-dementia. N Engl J Med. 1978;299:680–685. doi: 10.1056/NEJM197809282991302.
- Holloway R. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol. 2009;66:563–570. doi: 10.1001/archneurol.2009.32.
- Kohler S, Thiel A. Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. Blood. 2009;113:769–774. doi: 10.1182/blood-2008-02-139154.
- Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A (1999) The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse. Exp Neurol 156:50–61
- Lebouvier T, Neunlist M, VS Bd, Coron E, Drouard A, N’Guyen JM, Chaumette T, Tasselli M, Paillusson S, Flamand M, Galmiche JP, Damier P, Derkinderen P. Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms. PLoS One. 2010;5:e12728. doi: 10.1371/journal.pone.0012728.
- Leddy AL, Crowner BE, Earhart GM. Functional gait assessment and balance evaluation system test: reliability, validity, sensitivity, and specificity for identifying individuals with Parkinson disease who fall. Phys Ther. 2011;91:102–113. doi: 10.2522/ptj.20100113.
- Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, de St F, Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–1711. doi: 10.1084/jem.20060772.
- McGeer PL, McGeer EG. Glial reactions in Parkinson’s disease. Mov Disord. 2008;23:474–483. doi: 10.1002/mds.21751.
- McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988;38:1285–1291. doi: 10.1212/WNL.38.8.1285.
- Miyawaki T, Uehara T, Nibu R, Tsuji T, Yachie A, Yonehara S, Taniguchi N. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol. 1992;149:3753–3758.
- Mosley RL, Hutter-Saunders JA, Stone DK, Gendelman HE. Inflammation and adaptive immunity in Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2:a009381.
- Newton-Nash DK, Newman PJ. A new role for platelet-endothelial cell adhesion molecule-1 (CD31): inhibition of TCR-mediated signal transduction. J Immunol. 1999;163:682–688.
- Oyaizu N, McCloskey TW, Than S, Hu R, Kalyanaraman VS, Pahwa S. Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-alpha secretion. Blood. 1994;84:2622–2631.
- Pepper M, Jenkins MK. Origins of CD4(+) effector and central memory T cells. Nat Immunol. 2011;12:467–471. doi: 10.1038/ni.2038.
- Pouplard A, Emile J. Autoimmunity in Parkinson’s disease. Adv Neurol. 1984;40:307–313.
- Rentzos M, Evangelopoulos E, Sereti E, Zouvelou V, Marmara S, Alexakis T, Evdokimidis I. Alterations of T cell subsets in ALS: a systemic immune activation? Acta Neurol Scand. 2012;125:260–264. doi: 10.1111/j.1600-0404.2011.01528.x.
- Reynolds AD, Kadiu I, Garg SK, Glanzer JG, Nordgren T, Ciborowski P, Banerjee R, Gendelman HE. Nitrated alpha-synuclein and microglial neuroregulatory activities. J Neuroimmune Pharmacol. 2008;3:59–74. doi: 10.1007/s11481-008-9100-z.
- Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol. 2010;184:2261–2271. doi: 10.4049/jimmunol.0901852.
- Rosenkranz D, Weyer S, Tolosa E, Gaenslen A, Berg D, Leyhe T, Gasser T, Stoltze L. Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J Neuroimmunol. 2007;188:117–127. doi: 10.1016/j.jneuroim.2007.05.011.
- Ross EA, Coughlan RE, Flores-Langarica A, Bobat S, Marshall JL, Hussain K, Charlesworth J, Abhyankar N, Hitchcock J, Gil C, Lopez-Macias C, Henderson IR, Khan M, Watson SP, MacLennan IC, Buckley CD, Cunningham AF. CD31 is required on CD4+ T cells to promote T cell survival during Salmonella infection. J Immunol. 2011;187:1553–1565. doi: 10.4049/jimmunol.1000502.
- Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708–712. doi: 10.1038/44385.
- Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–763. doi: 10.1146/annurev.immunol.22.012703.104702.
- Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, de St F, Groth B. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203:1693–1700. doi: 10.1084/jem.20060468.
- Soler D, Chapman TR, Poisson LR, Wang L, Cote-Sierra J, Ryan M, McDonald A, Badola S, Fedyk E, Coyle AJ, Hodge MR, Kolbeck R. CCR8 expression identifies CD4 memory T cells enriched for FOXP3+ regulatory and Th2 effector lymphocytes. J Immunol. 2006;177:6940–6951.
- Strang RR. The association of gastro-duodenal ulceration and Parkinson’s disease. Med J Aust. 1965;1:842–843.
- Yonkers NL, Sieg S, Rodriguez B, Anthony DD. Reduced naive CD4 T cell numbers and impaired induction of CD27 in response to T cell receptor stimulation reflect a state of immune activation in chronic hepatitis C virus infection. J Infect Dis. 2011;203:635–645. doi: 10.1093/infdis/jiq101.
- Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhou Y, Hong JS, Zhang J. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 2005;19:533–542. doi: 10.1096/fj.04-2751com.
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