Immune Regulation by Self-Reactive T Cells is Antigen Specific

Tanchot, Corinne; Vasseur, Florence; Pontoux, Christiane; Garcia, Cyrielle; Sarukhan, Adélaïda

doi:10.4049/jimmunol.172.7.4285

Cited by 62 publications

(53 citation statements)

References 32 publications

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“…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.…”

Section: Discussionmentioning

confidence: 75%

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

Yan

Garg

Banerjee

2010

Journal of Biological Chemistry

106

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Section: Discussionmentioning

confidence: 75%

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

Yan

Garg

Banerjee

2010

Journal of Biological Chemistry

106

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“…The second point is that reactivation of Treg cells triggers cytokine production and overrides restriction for specificity. This may be the underlying mechanism for the controversial observations regarding specificity of Treg-suppressive function (14,34,37,38). Also, a similar mechanism could be responsible for the differential Treg function associated with their activation status (39).…”

Section: Discussionmentioning

confidence: 99%

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

Yü

Gregg

Bell

et al. 2005

The Journal of Immunology

112

102

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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.

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“…CNS-derived T-reg also showed enhanced production of IL-10. It has been proposed that natural T-reg only regulate T-eff bearing TcRs for the same antigen 39 . Also, adoptive transfer of myelin basic protein (MBP) TcR-transgenic CD4 + CD25 + T-reg, but not of non-specific T-reg, into MBP TcR-transgenic Rag-deficient recipients prevents the development of spontaneous EAE when the cells are transferred before disease onset 40 .…”

Section: Discussionmentioning

confidence: 99%

Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation

Korn

Reddy

Gao

et al. 2007

Nat Med

754

723

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Treatment with ex vivo-generated regulatory T cells (T-reg) has been regarded as a potentially attractive therapeutic approach for autoimmune diseases. However, the dynamics and function of T-reg in autoimmunity are not well understood. Thus, we developed Foxp3gfp knock-in (Foxp3gfp.KI) mice and myelin oligodendrocyte glycoprotein (MOG) /IAb (MHC class II) tetramers to track autoantigen-specific effector T cells (T-eff) and T-reg in vivo during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. MOG tetramer-reactive, Foxp3 + T-reg expanded in the peripheral lymphoid compartment and readily accumulated in the central nervous system (CNS), but did not prevent the onset of disease. Foxp3 + T cells isolated from the CNS were effective in suppressing naive MOG-specific T cells, but failed to control CNS-derived encephalitogenic T-eff that secreted interleukin (IL)-6 and tumor necrosis factor (TNF). Our data suggest that in order for CD4 + Foxp3 + T-reg to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation.Thymus-derived (natural) T-reg are crucial for preventing generalized multiorgan autoimmunity throughout the lifespan of an individual 1,2 . The importance of antigenspecific T-reg in conferring genetic resistance to organ-specific autoimmunity 3 COMPETING INTERESTS STATEMENTThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions NIH Public Access 10,11 .In vitro, natural T-reg are anergic and suppress T-eff responses in a cell contact-dependent manner 12 . In vivo, T-reg can proliferate and their mechanism of suppression remains largely unknown 13,14 . It was suggested that the encounter with autoantigens was required for their maintenance in vivo 15 . However, it is unclear whether expansion of antigen-specific T-reg can actually be triggered during an inflammatory autoimmune response. This is a fundamental question as T-reg that bear transgenic autoreactive T-cell receptors (TcRs) seem to suppress autoimmune diabetes better than a polyclonal T-reg population does 16 . Furthermore, it has been shown that naive T cells develop reciprocally into T-reg or pathogenic T-helper type 17 (T H 17) cells depending on the absence or presence of IL-6 in the local cytokine milieu [17][18][19] . Thus, the origin and population dynamics of T-reg in autoimmune tissue inflammation are unclear. It has been proposed that in EAE, T-reg may not even reach the target organ but may prevent the trafficking of autopathogenic T-eff into the CNS (ref. The transcription factor Foxp3 has been identified as crucial for the commitment of thymocytes to the T-reg lineage [21][22][23] . We and others have generated Foxp3gfp.KI mice in order to reliably monitor T-reg in vivo based on the linked expression of green fluorescent protein (GFP) in Foxp3 + T cells 19,24 . Using Foxp3gfp.KI mice in combination with a MOG 35-55 /IAb-specifi...

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Immune Regulation by Self-Reactive T Cells is Antigen Specific

Cited by 62 publications

References 32 publications

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

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

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

Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation

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