Specific T Regulatory Cells Display Broad Suppressive Functions against Experimental Allergic Encephalomyelitis upon Activation with Cognate Antigen

Abstract

To date, very few Ag-based regimens have been defined that could expand T regulatory (Treg) cells to reverse autoimmunity. Additional understanding of Treg function with respect to specificity and broad suppression should help overcome these limitations. Ig-proteolipid protein (PLP)1, an Ig carrying a PLP1 peptide corresponding to amino acid residues 139-151 of PLP, displayed potent tolerogenic functions and proved effective against experimental allergic encephalomyelitis (EAE). In this study, we took advantage of the Ig-PLP1 system and the PLP1-specific TCR transgenic 5B6 mouse to define a regimen that could expand Ag-specific Treg cells in vivo and tested for effectiveness against autoimmunity involving diverse T cell specificities. The findings indicate that in vivo exposure to aggregated Ig-PLP1 drives PLP1-specific 5B6 TCR transgenic cells to evolve as Treg cells expressing CD25, CTLA-4, and Foxp3 and producing IL-10. These Treg cells were able to suppress PLP1 peptide-induced EAE in both SJL/J and F1 (SJL/J × C57BL/6) mice. However, despite being effective against disease induced with a CNS homogenate, the Treg cells were unable to counter EAE induced by a myelin basic protein or a myelin oligodendrocyte glycoprotein peptide. Nevertheless, activation with Ag before transfer into the host mice supports suppression of both myelin oligodendrocyte glycoprotein- and myelin basic protein peptide-induced EAE. Thus, it is suggested that activation of Treg cells by the cognate autoantigen is necessary for operation of broad suppressive functions.

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

“…Based on our preliminary results, we propose that the reduced autoimmunity in the EAE model and in the anti-DNA transgenic mouse model is due to increased effectiveness of regulatory T cells in the absence of CD5 derived signals. This is supported by several papers demonstrating the importance of nT reg numbers and function in the regulation of EAE (50,51).…”

Decreased production of TNF-alpha by lymph node cells indicates experimental autoimmune encephalomyelitis remission in Lewis rats

“…Thus, it is possible that many of these cells are not specific for myelin. This possibility is supported by the detection of a broad and non-specific regulatory effect of Treg cells in EAE (Yu et al 2005).…”

Regulatory T Cells Interfere with Glutathione Metabolism in Dendritic Cells and T Cells

“…Although several studies suggest that Tregs suppress in an antigen-restricted manner in vitro and in vivo (32)(33)(34), others report that Tregs do not require specific TCR-antigen interaction for suppression of Teff proliferation (35,36). We have demonstrated that although remodeling of the extracellular environment by Tregs is antigen-dependent, it is not antigen-specific.…”