scholarly journals Regulatory T Cells Maintain Long-Term Tolerance to Myelin Basic Protein by Inducing a Novel, Dynamic State of T Cell Tolerance

2007 ◽  
Vol 178 (2) ◽  
pp. 887-896 ◽  
Author(s):  
Sarah E. Cabbage ◽  
Eric S. Huseby ◽  
Blythe D. Sather ◽  
Thea Brabb ◽  
Denny Liggitt ◽  
...  
2009 ◽  
Vol 107 (1) ◽  
pp. 199-203 ◽  
Author(s):  
A. Schildknecht ◽  
S. Brauer ◽  
C. Brenner ◽  
K. Lahl ◽  
H. Schild ◽  
...  

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 568-568
Author(s):  
Krystalyn E. Hudson ◽  
James C. Zimring

Introduction: Loss of humoral tolerance to red blood cell (RBC) antigens may lead to the generation of pathogenic autoantibodies and result in autoimmune hemolytic anemia (AIHA), a severe and potentially fatal disease. Failure of tolerance to RBC antigens occurs with considerable frequency (1-3 cases/1,000 adults) and prevalence of AIHA is as high as 30% in persons with compromised B and/or T cell tolerance mechanisms. However, RBC-specific tolerance mechanisms are poorly understood. To elucidate the immune tolerances to RBC autoantigens, we utilized HOD mice. The HOD mouse expresses an RBC-specific transgene consisting of hen egg lysozyme (HEL), ovalbumin (OVA), and Duffy. Using the HOD model, we previously demonstrated B cell tolerance to RBC-specific HOD antigen is incomplete; however, T cell tolerance is stringent. HOD mice have similar detectable frequencies of HOD-specific CD4+ T cells compared to B6 mice. Although present, autoreactive HOD-specific CD4+ T cells are non-functional. Circumventing T cell tolerance by adoptive transfer, HOD mice make high titer anti-HOD autoantibodies in vivo. Thus, despite the presence of autoreactive B cells, no HOD-reactive antibodies are detectable unless CD4+ T cells are given, indicating T cell tolerance is a stopgap to autoimmunity. Methods: Leukocytes from C57BL/6 (B6) and HOD mice were harvested and OVA-specific CD4+ T cell responses were assessed by tetramer-pulldown assays with pooled tetramers I-Ab-OVA 329-337/326-334. Isolated cells were stained for surface and intracellular markers and analyzed via flow cytometry. For in vivo analysis, mice were treated with 300ug anti-CD25 (clone PC-61) depleting antibody or isotype control; a subset of antibody-treated mice was immunized with OVA/CFA. Antibodies bound to HOD RBCs were determined by direct antibody test. Anti-HOD antibodies were quantified by indirect immunofluorescence using HOD RBCs as targets. Results: Tetramer pull-down assays revealed similar numbers of OVA-reactive CD4+ T cells from HOD and B6 mice (mean 56 and 40, respectively, p = 0.3). However, cell surface and intracellular marker staining demonstrated that HOD mice had higher numbers of OVA-tetramer reactive CD4+ T cells that express regulatory markers CD25 and FoxP3, and exhaustion marker PD1 as compared to control B6 mice. Inhibitory CTLA4 expression was not detectable on OVA-reactive CD4+ T cells from HOD or B6 mice. To test whether regulatory T cells were required for RBC-specific immune tolerance, HOD and B6 mice were treated with CD25 depleting antibody or isotype control antibody. Anti-CD25 antibody treated mice had a significant reduction of CD25+ cells 4 days post treatment (p < 0.001, 2 independent experiments). Similarly, there was a significant reduction in FoxP3+CD25+CD4+ T cells (Tregs) in anti-CD25 treated mice (p < 0.001), compared to isotype. Mice received weekly injections of anti-CD25 or isotype antibody to maintain depletion for one month. A subset of mice received an OVA/CFA immunization. Sustained CD25+ depletion did not result in anti-HOD autoantibody generation. Further, there was no change in the endogenous frequency of OVA-reactive CD4+ T cells between HOD and B6 mice, regardless of antibody treatment. Similarly, HOD mice treated with depletion (or isotype) antibody and immunized with OVA/CFA did not make detectable anti-HOD autoantibodies. Consistent with lack of detectable autoantibodies, no expansion of OVA-tetramer reactive CD4+ T cells was observed in HOD mice. In contrast, B6 mice (treated with anti-CD25 or isotype antibody) had a detectable expansion of OVA-specific CD4+ T cells as a result of immunization. Conclusions: The data demonstrate a phenotypic difference between the OVA-reactive CD4+ T cells from HOD and B6 mice, with an increase in number of Tregs detectable in HOD mice. Administration of anti-CD25 antibody significantly reduced the number of overall CD25+ cells and Tregs. Prolonged depletion of these cellular subsets did not elicit autoantibodies in HOD mice. Further, immunization of CD25 depleted mice with a strong immune stimulus (OVA/CFA, known to expand OVA-reactive T cells in B6 mice), did not induce anti-HOD autoantibodies nor did it expand OVA-specific autoreactive CD4+ T cells in HOD mice. Together, these data demonstrate that CD25+ cells are not required for the maintenance of RBC-specific T cell tolerance and suggest a role for other regulatory mechanisms. Disclosures No relevant conflicts of interest to declare.


Hepatology ◽  
2009 ◽  
Vol 50 (2) ◽  
pp. 612-621 ◽  
Author(s):  
Ekaterina Breous ◽  
Suryanarayan Somanathan ◽  
Luk H. Vandenberghe ◽  
James M. Wilson

2006 ◽  
Vol 176 (6) ◽  
pp. 3410-3416 ◽  
Author(s):  
Daron Forman ◽  
Eun-Suk Kang ◽  
Chaorui Tian ◽  
Jesus Paez-Cortez ◽  
John Iacomini

Immunity ◽  
2015 ◽  
Vol 43 (5) ◽  
pp. 896-908 ◽  
Author(s):  
Francois P. Legoux ◽  
Jong-Baeck Lim ◽  
Andrew W. Cauley ◽  
Stanislav Dikiy ◽  
James Ertelt ◽  
...  

2008 ◽  
Vol 68 (1) ◽  
pp. 292-300 ◽  
Author(s):  
Elena Degl'Innocenti ◽  
Matteo Grioni ◽  
Giusy Capuano ◽  
Elena Jachetti ◽  
Massimo Freschi ◽  
...  

Immunity ◽  
2001 ◽  
Vol 14 (4) ◽  
pp. 471-481 ◽  
Author(s):  
Eric S. Huseby ◽  
Blythe Sather ◽  
Priya G. Huseby ◽  
Joan Goverman

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