PD1 negative and PD1 positive CD4+ T regulatory cells in mild cognitive impairment and Alzheimer's disease.

Regulatory T lymphocytes (Treg) play a fundamental importance in modulating the relative balance between inflammation and immune tolerance, and alterations of these cells are observed in inflammatory diseases. To better characterize the neuroinflammatory processes suggested to be associated with Alzheimer's disease (AD) and to clarify the possible role of Treg cells in this process, we extensively analyzed these cells (CD4 + CD25highFoxp3+) in patients with either severe AD (n=25) or mild cognitive impairment (MCI) (n=25), comparing the results with those of two groups of healthy controls (HC) (n=55). Because the intra- or extracellular expression of programmed death receptor 1 (PD1) identifies functionally diverse subsets of Treg we also analyzed such subpopulations. Results showed that, whereas both Treg and PD1pos Treg are increased in MCI and AD patients compared to HC, PD1neg Treg, the subpopulation of Treg cells endowed with the strongest suppressive ability, are significantly augmented in MCI patients alone. In these patients amyloid-β-stimulated-T cells proliferation was reduced and Treg-mediated suppression was more efficient compared to both AD and HC. The observation that PD1neg Treg, cells are increased in MCI patients reinforces the inflammatory origin of AD and supports a possible beneficial role of these cells in MCI that is lost in patients with full-blown AD.

[1]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease: Report of the NINCDS—ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease , 2011, Neurology.

[2]  T. Town,et al.  CNS Infiltration of Peripheral Immune Cells: D-Day for Neurodegenerative Disease? , 2009, Journal of Neuroimmune Pharmacology.

[3]  Marina A. Lynch,et al.  The Multifaceted Profile of Activated Microglia , 2009, Molecular Neurobiology.

[4]  J. McLaurin,et al.  Selective targeting of perivascular macrophages for clearance of β-amyloid in cerebral amyloid angiopathy , 2009, Proceedings of the National Academy of Sciences.

[5]  R. Maserati,et al.  Myelin basic protein-specific T lymphocytes proliferation and programmed cell death in demyelinating diseases. , 2008, Clinical immunology.

[6]  C. Palencia,et al.  Fibrillar Amyloid-β Peptides Activate Microglia via TLR2: Implications for Alzheimer’s Disease1 , 2008, The Journal of Immunology.

[7]  K. Kohyama,et al.  Nonviral DNA Vaccination Augments Microglial Phagocytosis of &bgr;-Amyloid Deposits as a Major Clearance Pathway in an Alzheimer Disease Mouse Model , 2008, Journal of neuropathology and experimental neurology.

[8]  Jun Tan,et al.  Blocking TGF-β–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology , 2008, Nature Medicine.

[9]  M. O’Banion,et al.  Chronic Interleukin-1β Expression in Mouse Brain Leads to Leukocyte Infiltration and Neutrophil-Independent Blood–Brain Barrier Permeability without Overt Neurodegeneration , 2007, The Journal of Neuroscience.

[10]  P. Rossini,et al.  Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. , 2007, Blood.

[11]  C. Tinelli,et al.  Lymphocyte subset patterns and cytokine production in Alzheimer's disease patients , 2007, Neurobiology of Aging.

[12]  L. Stoltze,et al.  Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration , 2007, Journal of Neuroimmunology.

[13]  V. Kuchroo,et al.  Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression , 2007, The Journal of experimental medicine.

[14]  K. Venken,et al.  A CFSE based assay for measuring CD4+CD25+ regulatory T cell mediated suppression of auto-antigen specific and polyclonal T cell responses. , 2007, Journal of immunological methods.

[15]  Michael T. Heneka,et al.  Inflammatory processes in Alzheimer's disease , 2007, Journal of Neuroimmunology.

[16]  L. Walker,et al.  The role of CD28 and cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) in regulatory T‐cell biology , 2006, Immunological reviews.

[17]  J. Myśliwska,et al.  CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence. , 2006, Clinical immunology.

[18]  A. Thomson,et al.  Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells1 , 2006, The Journal of Immunology.

[19]  T. Town,et al.  Journal of Neuroinflammation BioMed Central Review Involvement of β-chemokines in the development of inflammatory demyelination , 2005 .

[20]  H. Chiu,et al.  The association between promoter polymorphism of the interleukin-10 gene and Alzheimer's disease , 2005, Neurobiology of Aging.

[21]  J. Bluestone,et al.  Distinct roles of CTLA‐4 and TGF‐β in CD4+CD25+ regulatory T cell function , 2004 .

[22]  S. Sakaguchi,et al.  CD4+ Tregs and immune control. , 2004, The Journal of clinical investigation.

[23]  C. Jack,et al.  Mild cognitive impairment – beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment , 2004, Journal of internal medicine.

[24]  R. Petersen Mild cognitive impairment as a diagnostic entity , 2004, Journal of internal medicine.

[25]  Nitin J. Karandikar,et al.  High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. , 2004, Blood.

[26]  J. Witkowski,et al.  Decreased proliferative capability of CD4+ cells of elderly people is associated with faster loss of activation-related antigens and accumulation of regulatory T cells , 2004, Experimental Gerontology.

[27]  S. Sakaguchi Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. , 2004, Annual review of immunology.

[28]  J. Alcocer-Varela,et al.  Quantification of regulatory T cells in patients with systemic lupus erythematosus. , 2003, Journal of autoimmunity.

[29]  D. Taramelli,et al.  1–40 β‐amyloid protein fragment modulates the expression of CD44 and CD71 on the astrocytoma cell line in the presence of IL1β and TNFα , 2003 .

[30]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[31]  B. Small,et al.  CD45 isoform alteration in CD4+ T cells as a potential diagnostic marker of Alzheimer's disease , 2002, Journal of Neuroimmunology.

[32]  M. Mullan,et al.  CD40-CD40L interaction in Alzheimer's disease. , 2002, Current opinion in pharmacology.

[33]  M. Shoji,et al.  Cerebrospinal fluid Abeta40 and Abeta42: natural course and clinical usefulness. , 2002, Frontiers in bioscience : a journal and virtual library.

[34]  L Scola,et al.  Gender-specific association between −1082 IL-10 promoter polymorphism and longevity , 2002, Genes and Immunity.

[35]  R. Ciubotariu,et al.  CD8+CD28− T suppressor cells and the induction of antigen‐specific, antigen‐presenting cell‐mediated suppression of Th reactivity , 2001, Immunological reviews.

[36]  A. Weverling-Rijnsburger,et al.  Patients with Alzheimer's disease display a pro-inflammatory phenotype , 2001, Experimental Gerontology.

[37]  A. B. Lyons,et al.  Analysing cell division in vivo and in vitro using flow cytometric measurement of CFSE dye dilution. , 2000, Journal of immunological methods.

[38]  J. Shimizu,et al.  Naturally anergic and suppressive CD25(+)CD4(+) T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. , 2000, International immunology.

[39]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[40]  C. Patlak,et al.  In Vitro Evidence That β‐Amyloid Peptide 1–40 Diffuses Across the Blood–Brain Barrier and Affects Its Permeability , 2000, Journal of neuropathology and experimental neurology.

[41]  E. Ferrari,et al.  Overproduction of IFN‐γ and TNF‐α from Natural Killer (NK) Cells Is Associated with Abnormal NK Reactivity and Cognitive Derangement in Alzheimer's Disease , 2000 .

[42]  Y. Wu,et al.  Induction of CD40 on human endothelial cells by Alzheimer’s β-amyloid peptides , 1999, Brain Research Bulletin.

[43]  R. Cacabelos,et al.  Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer's Disease (AD) individuals , 1999, Journal of Neuroimmunology.

[44]  T. Makinodan,et al.  Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12 , 1999, Experimental Gerontology.

[45]  V. Singh,et al.  Circulating cytokines in Alzheimer's disease. , 1997, Journal of psychiatric research.

[46]  R. Rydel,et al.  Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[47]  C. Brodie,et al.  T lymphocyte subpopulations and activation markers correlate with severity of Alzheimer's disease. , 1995, Clinical immunology and immunopathology.

[48]  H. Müller-Hermelink,et al.  Admission criteria for immunogerontological studies in man: The senieur protocol , 1984, Mechanisms of Ageing and Development.

[49]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[50]  C. P. Hughes,et al.  A New Clinical Scale for the Staging of Dementia , 1982, British Journal of Psychiatry.

[51]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[52]  G. Pawelec,et al.  Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer's disease. , 2009, Journal of Alzheimer's disease : JAD.

[53]  R. Maccioni,et al.  Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. , 2008, Archives of medical research.

[54]  S. Kim-Schulze,et al.  Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells: review. , 2005, International immunopharmacology.

[55]  J. Bluestone,et al.  Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. , 2004, European journal of immunology.

[56]  D. Taramelli,et al.  1-40 Beta-amyloid protein fragment modulates the expression of CD44 and CD71 on the astrocytoma cell line in the presence of IL1beta and TNFalpha. , 2003, Journal of cellular physiology.

[57]  A. Rudensky,et al.  Foxp 3 programs the development and function of CD 4 + CD 25 + regulatory T cells , 2003 .

[58]  S. Hori,et al.  Control of autoimmunity by naturally arising regulatory CD4+ T cells. , 2003, Advances in immunology.

[59]  Svetlana Ten,et al.  Multiple immuno-regulatory defects in type-1 diabetes. , 2002, The Journal of clinical investigation.

[60]  Y. Wu,et al.  Induction of CD40 on human endothelial cells by Alzheimer's beta-amyloid peptides. , 1999, Brain research bulletin.