Regulator T Cells: Specific for Antigen and/or Antigen Receptors?

MyD88 is an adaptor molecule that functions in the innate signaling induced by proinflammatory adjuvants that interact with TLRs. Mice lacking MyD88, for example, resist active experimental autoimmune encephalomyelitis (EAE) induced by immunization with an encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide in CFA. We reasoned that MyD88−/− mice, nevertheless, should be susceptible to EAE mediated by adoptive transfer of activated encephalitogenic T cell lines, which do not require adjuvant signaling for their effector functions. We now report, however, that mice lacking MyD88 also resist adoptive EAE mediated by an anti-MOG T cell line that is strongly encephalitogenic in wild-type (WT) mice. The transferred anti-MOG T cells proliferated, secreted INF-γ, and migrated to the CNS in the MyD88−/− mice, as they did in WT mice, but inflammatory infiltrates did not progress and clinical EAE did not develop. The resistance of the MyD88−/− mice to adoptive EAE mediated by the otherwise encephalitogenic T cells was found to result from the secretion of IL-10 by recipient T cells of two different specificities: those specific for MOG and those responding to the T cell clone itself—both anticlonotypic and antiergotypic T regulators were detected. IL-10–producing anti-MOG T cells isolated from immunized MyD88−/− mice suppressed the induction of active EAE in WT recipients. Moreover, the absence of IL-10 production in MyD88/IL-10 double-knockout mice rendered the mice susceptible to adoptive transfer of EAE. Thus, MyD88 signaling appears to be a key factor in determining the cytokine phenotype of T cells involved in autoimmune inflammation and regulation.

Section: Discussionmentioning

confidence: 99%

Section: Cd3mentioning

confidence: 99%

IL-10 Mediates Resistance to Adoptive Transfer Experimental Autoimmune Encephalomyelitis in MyD88−/− Mice

Cohen

Nussbaum³

2009

“…Other mechanisms could include decreased concentration of self Ag, exhaustion of autoreactive effectors, molecular and cellular feedback circuits that decrease the number or function of specific lymphocyte subsets different from T R via apoptosis, tuning of the repertoire (28), and/or the induction of CD8 ϩ suppressors (29). Regarding this last possibility, Fan and Singh (30) reported that genetic vaccination with minigenes encoding NZB/W F 1 anti-DNA (V H -derived) MHC class I-binding epitopes activated cytotoxic CD8 ϩ T lymphocytes, which lysed autoantibody-producing NZB/W F 1 B cells, with subsequent protection from SLE.…”

Section: Cd4mentioning

confidence: 99%

Ig-Reactive CD4+CD25+ T Cells from Tolerized (New Zealand Black × New Zealand White)F1 Mice Suppress In Vitro Production of Antibodies to DNA

Cava

Ebling

Hahn

2004

We have recently shown that tolerogenic administration of an artificial peptide (pConsensus) that is based on sequences within the VH regions of several murine anti-dsDNA Ig delays appearance of autoantibodies in female (New Zealand Black (NZB) × New Zealand White (NZW))F1 (NZB/W F1) mice and significantly prolongs their survival. The aim of this study was to characterize the T cell population(s) involved in pConsensus-induced down-regulation of autoimmune responses in tolerized NZB/W F1 mice. Using MHC class II dimers loaded with tolerogenic peptide, we found that pCons favored expansion of peptide-reactive CD4+CD25+ regulatory T cells (TR) that inhibited in vitro production of anti-dsDNA Ab-forming cells. Suppression by TR was abrogated by the presence in culture of Ab to glucocorticoid-induced TNFR family member 18 or to TGFβ latency-associated protein. These findings suggest possible relevance of Ag specificity in the mechanism of TR-mediated immune tolerance to Ig-derived peptides in NZB/W F1 mice.

“…25). However, if syngeneic mice are preimmunized with Mito-C-treated lymphoma cells, they become resistant to the tumor cells used for vaccination (23)(24)(25). To get more insight into the mechanism of induction of the protective immune response, B6 mice were immunized with different doses of L12R4 M cells as described in Materials and Methods.…”

Section: Induction Of Protective Immunity Against L12r4 Cellsmentioning

confidence: 99%

“…CD8 ϩ T cells have also been suggested to play such a role, but in these studies either the function, specificity, or MHC restriction of the CD8 ϩ cells were not reported (14,21,22). We have found previously 1) that TCR-specific CD8 ϩ T cells play a significant biological role in the regulation of experimental autoimmune encephalomyelitis (EAE) 3 (23,24) and 2) that mice vaccinated with mitomycin C (Mito-C)-treated T lymphoma cells were resistant to new challenge with the same T lymphoma cells and that this immunity may be TCR specific (24,25). In the present study, we have tried to elucidate the different parameters of an immune response to TCR chains: 1) the lymphocytes involved in the initiation and effector phases of the response, 2) the mechanism of the effector phase, and 3) the fine specificity and MHC restriction of the effector cells.…”

mentioning

confidence: 99%

Self-Reactive T Cell Receptor-Reactive CD8+ T Cells Inhibit T Cell Lymphoma Growth In Vivo

Gonthier

Llobera

Arnaud

et al. 2004

Syngenic C57BL/6 mice (H-2b) vaccinated with mitomycin C-treated L12R4 T lymphoma cells develop protective immunity toward the MHC class II-negative tumor cells. In the present study, we characterize the nature, mode of function, and specificity of the effector cells in this immunity. These cells are TCR-specific CD8+ T lymphocytes with effector function in vitro as well as in vivo upon transfer to naive mice. They produce high levels of IFN-γ and TNF-α, but little or no IL-4. By means of TCRβ-negative variant L12R4 cells, P3.3, and TCR-Vβ2 cDNA-transfected and TCR-Vβ2-expressing P3.3 lymphoma cells, we found that a significant part of the effector T cells are specific for the Vβ12 region. The growth inhibition of L12R4 cells in vitro was inhibited by anti-H-2, anti-Kb, and anti-Db mAb. Furthermore, vaccination with Vβ12 peptide p67–78, which binds to both Kb and Db MHC class I molecules, induces partial protection against L12R4 T lymphoma cells. Thus, self-reactive TCR-Vβ-specific, Kb-, or Db-restricted CD8+ T cells mediate inhibition of T cell lymphoma growth in vitro and in vivo.