Orally tolerized T cells can form conjugates with APCs but are defective in immunological synapse formation.
Oral tolerance is systemic immune hyporesponsiveness induced by the oral administration of soluble Ags. Hyporesponsiveness of Ag-specific CD4 T cells is responsible for this phenomenon. However, the molecular mechanisms underlying the hyporesponsive state of these T cells are not fully understood. In the present study, we investigated the ability of orally tolerized T cells to form conjugates with Ag-bearing APCs and to translocate TCR, protein kinase C-theta (PKC-theta), and lipid rafts into the interface between T cells and APCs. Orally tolerized T cells were prepared from the spleens of OVA-fed DO11.10 mice. Interestingly, the orally tolerized T cells did not show any impairment in the formation of conjugates with APCs. The conjugates were formed in a LFA-1-dependent manner. Upon antigenic stimulation, the tolerized T cells could indeed activate Rap1, which is critical for LFA-1 activation and thus cell adhesion. However, orally tolerized T cells showed defects in the translocation of TCR, PKC-theta, and lipid rafts into the interface between T cells and APCs. Translocation of TCR and PKC-theta to lipid raft fractions upon antigenic stimulation was also impaired in the tolerized T cells. Ag-induced activation of Vav, Rac1, and cdc42, which are essential for immunological synapse and raft aggregation, were down-regulated in orally tolerized T cells. These results demonstrate that orally tolerized T cells can respond to specific Ags in terms of conjugate formation but not with appropriate immunological synapse formation. This may account for the hyporesponsive state of orally tolerized T cells.
Department of Applied Biological Chemistry, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Wataru
W
Ise
Kentaro
K
Nakamura
Nobuko
N
Shimizu
Hirofumi
H
Goto
Kenichiro
K
Fujimoto
Shuichi
S
Kaminogawa
Satoshi
S
Hachimura
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000637:transplantation*; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D007527:Isoenzymes / Q000172:deficiency / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011493:Protein Kinase C / Q000172:deficiency / Q000378:metabolism; D000074121:Protein Kinase C-theta; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000172:deficiency / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000378:metabolism
D018797:Cell Cycle Proteins; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse; D010047:Ovalbumin; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein