Instant effect of soluble antigen on effector T cells in peripheral immune organs during immunotherapy of autoimmune encephalomyelitis

i.v. infusion of native autoantigen or its altered peptide variants is an important therapeutic option for the treatment of autoimmune diseases, because it selectively targets the disease-inducing T cells. To learn more about the mechanisms and kinetics of this approach, we visualized the crucial initial effects of i.v. infusion of peptides or intact protein on GFP-tagged autoaggressive CD4+ effector T cells using live-video and two-photon in situ imaging of spleens in living animals. We found that the time interval between i.v. injection of intact protein to first changes in T cell behavior was extremely short; within 10 min after protein application, the motility of the T cells changed drastically. They slowed down and became tethered to local sessile stromal cells. A part of the cells aggregated to form clusters. Within the following 20 min, IFN-γ mRNA was massively (>100-fold) up-regulated; surface IL-2 receptor and OX-40 (CD 134) increased 1.5 h later. These processes depleted autoimmune T cells in the blood circulation, trapping the cells in the peripheral lymphoid organs and thus preventing them from invading the CNS. This specific blockage almost completely abrogated CNS inflammation and clinical disease. These findings highlight the speed and efficiency of antigen recognition in vivo and add to our understanding of T cell-mediated autoimmunity.

[1]  R. Mebius,et al.  Structure and function of the spleen , 2005, Nature Reviews Immunology.

[2]  H. Lassmann,et al.  Autoimmune CD4+ T Cell Memory: Lifelong Persistence of Encephalitogenic T Cell Clones in Healthy Immune Repertoires 1 , 2005, The Journal of Immunology.

[3]  Tobias Bonhoeffer,et al.  Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion , 2005, The Journal of experimental medicine.

[4]  Michael Sixt,et al.  The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. , 2005, Immunity.

[5]  Ira Mellman,et al.  Cell biology of antigen processing in vitro and in vivo. , 2005, Annual review of immunology.

[6]  R. Hohlfeld,et al.  Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: From pipe dreams to (therapeutic) pipelines , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Michael D. Cahalan,et al.  Imaging the Single Cell Dynamics of CD4+ T Cell Activation by Dendritic Cells in Lymph Nodes , 2004, The Journal of experimental medicine.

[8]  Marc K Jenkins,et al.  Visualizing the first 50 hr of the primary immune response to a soluble antigen. , 2004, Immunity.

[9]  L. Fetler,et al.  Requirement of Rac1 and Rac2 Expression by Mature Dendritic Cells for T Cell Priming , 2004, Science.

[10]  A. Trautmann,et al.  ERM proteins regulate cytoskeleton relaxation promoting T cell–APC conjugation , 2004, Nature Immunology.

[11]  R. Ransohoff,et al.  The Activation Status of Neuroantigen-specific T Cells in the Target Organ Determines the Clinical Outcome of Autoimmune Encephalomyelitis , 2004, The Journal of experimental medicine.

[12]  S. Henrickson,et al.  T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases , 2004, Nature.

[13]  P. Delmotte,et al.  Failure of basic protein therapy for multiple sclerosis , 1977, Journal of Neurology.

[14]  Lawrence Steinman,et al.  Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis , 2003, Nature Biotechnology.

[15]  M. Nolte,et al.  A Conduit System Distributes Chemokines and Small Blood-borne Molecules through the Splenic White Pulp , 2003, The Journal of experimental medicine.

[16]  R. Ransohoff,et al.  Three or more routes for leukocyte migration into the central nervous system , 2003, Nature Reviews Immunology.

[17]  Mark J. Miller,et al.  Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  A. Ben-nun,et al.  Multiantigen/multiepitope-directed immune-specific suppression of "complex autoimmune encephalomyelitis" by a novel protein product of a synthetic gene. , 2002, The Journal of clinical investigation.

[19]  Mark J. Miller,et al.  Two-Photon Imaging of Lymphocyte Motility and Antigen Response in Intact Lymph Node , 2002, Science.

[20]  W. Paul,et al.  Antigen challenge leads to in vivo activation and elimination of highly polarized TH1 memory T cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Miller,et al.  Epitope spreading in immune-mediated diseases: implications for immunotherapy , 2002, Nature Reviews Immunology.

[22]  Boris Barbour,et al.  Functional antigen-independent synapses formed between T cells and dendritic cells , 2001, Nature Immunology.

[23]  A. Khoruts,et al.  Single-cell analysis of signal transduction in CD4 T cells stimulated by antigen in vivo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  H. Lassmann,et al.  Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. , 2001, Immunity.

[25]  R. Pedotti,et al.  An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide , 2001, Nature Immunology.

[26]  Joseph Frank,et al.  Effective Antigen-Specific Immunotherapy in the Marmoset Model of Multiple Sclerosis , 2001, The Journal of Immunology.

[27]  C. Reis e Sousa,et al.  Microbial and T Cell-Derived Stimuli Regulate Antigen Presentation by Dendritic Cells In Vivo1 , 2000, The Journal of Immunology.

[28]  A. Evans,et al.  Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial , 2000, Nature Medicine.

[29]  J. Frank,et al.  Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand , 2000, Nature Medicine.

[30]  H. Wekerle,et al.  Gene transfer into CD4+ T lymphocytes: Green fluorescent protein-engineered, encephalitogenic T cells illuminate brain autoimmune responses , 1999, Nature Medicine.

[31]  Jide Tian,et al.  Antigen-based immunotherapy for autoimmune disease: from animal models to humans? , 1999, Immunology today.

[32]  P. Negulescu,et al.  Polarity of T cell shape, motility, and sensitivity to antigen. , 1996, Immunity.

[33]  H. Lassmann,et al.  The N-terminal domain of the myelin oligodendrocyte glycoprotein (MOG) induces acute demyelinating experimental autoimmune encephalomyelitis in the Lewis rat , 1995, Journal of Neuroimmunology.

[34]  G. Rodriguez,et al.  Destructive proteolysis by cysteine proteases in antigen presentation of ovalbumin , 1995, European journal of immunology.

[35]  J. Goverman,et al.  T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. , 1994, Science.

[36]  H. Geuze,et al.  Class II MHC molecules are present in macrophage lysosomes and phagolysosomes that function in the phagocytic processing of Listeria monocytogenes for presentation to T cells , 1992, The Journal of cell biology.

[37]  A. Trautmann,et al.  Imaging early steps of human T cell activation by antigen-presenting cells. , 1992, Journal of immunology.

[38]  W. Hickey,et al.  T‐lymphocyte entry into the central nervous system , 1991, Journal of neuroscience research.

[39]  H. Lassmann,et al.  Cellular immune reactivity within the CNS , 1986, Trends in Neurosciences.

[40]  H. Grey,et al.  Antigen recognition by H-2-restricted T cells. I. Cell-free antigen processing , 1983, The Journal of experimental medicine.

[41]  R. Lorenz,et al.  Myelin basic protein administration in multiple sclerosis. , 1973, Archives of neurology.

[42]  S. Levine,et al.  Allergic Encephalomyelitis: Passive Transfer Prevented by Encephalitogen , 1968, Science.