Neonatal injection of Lewis rats with recombinant Vβ8.2 induces T cell but not B cell tolerance and increased severity of experimental autoimmune encephalomyelitis

Vainiene, M.; Burrows, Gregory G.; Ariail, K.; Robey, Ian; Vandenbark, Arthur A.; Offner, H.

doi:10.1002/(sici)1097-4547(19960815)45:4<475::aid-jnr18>3.0.co;2-#

Cited by 18 publications

(8 citation statements)

References 20 publications

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“…TCR peptides derived mostly from the conserved complementarity determining region (CDR) and framework (Fr) regions of the TCR V β -chains have been found to be immunogenic in both animals and in humans (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Although the phenotype or the MHC restriction of Tregs has not been defined in most cases, it is clear that peptides from 2 distinct conserved regions, namely the Fr3 and CDR1/2 regions on the TCR V β 8.2 chain, can induce regulation and protection from antigen-induced EAE in both rats and B10.PL mice (15,26,27,29,30,(36)(37)(38)(39)(40).…”

Section: Specificity For Regulation Is Provided By the Recognition Ofmentioning

confidence: 98%

“…Although the phenotype or the MHC restriction of Tregs has not been defined in most cases, it is clear that peptides from 2 distinct conserved regions, namely the Fr3 and CDR1/2 regions on the TCR V β 8.2 chain, can induce regulation and protection from antigen-induced EAE in both rats and B10.PL mice (15,26,27,29,30,(36)(37)(38)(39)(40). It is noteworthy that in humans, both the CDR2 and Fr3 regions have been found to be immunogenic and can potentially induce Treg activity (34,35,41).…”

Section: Specificity For Regulation Is Provided By the Recognition Ofmentioning

confidence: 99%

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Homeostatic control of immunity by TCR peptide–specific Tregs

Kumar¹

2004

J. Clin. Invest.

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Regulation of the immune response is a multifaceted process involving lymphocytes that function to maintain both self tolerance as well as homeostasis following productive immunity against microbes. There are 2 broad categories of Tregs that function in different immunological settings depending upon the context of antigen exposure and the nature of the inflammatory response. During massive inflammatory conditions such as microbial exposure in the gut or tissue transplantation, regulatory CD4 + CD25 + Tregs broadly suppress priming and/or expansion of polyclonal autoreactive responses nonspecifically. In other immune settings where initially a limited repertoire of antigen-reactive T cells is activated and expanded, TCR-specific negative feedback mechanisms are able to achieve a fine homeostatic balance. Here I will describe experimental evidence for the existence of a Treg population specific for determinants that are derived from the TCR and are expressed by expanding myelin basic protein-reactive T cells mediating experimental autoimmune encephalomyelitis, an animal prototype for multiple sclerosis. These mechanisms ensure induction of effective but appropriately limited responses against foreign antigens while preventing autoreactivity from inflicting escalating damage. In contrast to CD25 + Tregs, which are most efficient at suppressing priming or activation, these specific Tregs are most efficient in controlling T cells following their activation. A historical perspective on specific Tregs in feedback regulationFeedback inhibition in macromolecular synthetic pathways has been described as the mechanism by which the end product either inhibits formation of or suppresses enzymes in its biosynthetic pathway, thus specifically limiting the accumulation of that end product. The idea proposed by Neils Jerne (1) that specialized lymphocytes might inhibit immune responses gave rise to the description of suppressor T cells in vitro in the 1960s and 1970s (2-5). Some of the initial indications of the existence of Tregs in vivo came from studies in the mid-1970s involving alloresponses wherein vaccination with polyclonal T lymphoblasts from a parental strain into F 1 hybrid rats abrogated anti-alloresponse and graft rejection (6, 7). These findings were followed by the demonstration that vaccination with an attenuated myelin basic proteinreactive (MBP-reactive) but not a purified protein derivative of mycobacterium-reactive cloned T cell line prevented MBP-induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats, further suggesting the induction of immunity against the antigen receptors on autoimmune lymphocytes (8). Cytotoxic CD8 + T cell lines capable of responding to T cells were induced in rats recovering from graft-versus-host disease or from T cell-mediated EAE (9, 10). Thus, killing of encephalitogenic CD4 + T cell lines in vitro by cytotoxic CD8 + as well as neutralization of their capacity in vivo to cause EAE clearly indicated that CD8 + Tregs recognizing some cell surface molecules on vaccinat...

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Section: Specificity For Regulation Is Provided By the Recognition Ofmentioning

confidence: 98%

Section: Specificity For Regulation Is Provided By the Recognition Ofmentioning

confidence: 99%

Homeostatic control of immunity by TCR peptide–specific Tregs

Kumar¹

2004

J. Clin. Invest.

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“…Ags: N-acetylated MBP 1-11 peptide (Ac-ASQKRPSQRSK) was synthesized by solid phase techniques and was purified by HPLC at the Beckman Institute, Stanford University (Stanford, CA). GST-BV8S2 proteins were expressed and purified as described previously (24). The GST-BV8S2 fusion protein contains the complete BV, BD, and BJ regions and the first 19 residues of the BC region from the TCR of an encephalitogenic rat T cell clone fused to the C-terminal end of GST.…”

Section: Micementioning

confidence: 99%

Reduced Chemokine and Chemokine Receptor Expression in Spinal Cords of TCR BV8S2 Transgenic Mice Protected Against Experimental Autoimmune Encephalomyelitis with BV8S2 Protein

Matejuk

Vandenbark

Burrows³

et al. 2000

The Journal of Immunology

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The perivascular transmigration and accumulation of macrophages and T lymphocytes in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) may be partly regulated by low m.w. chemotactic cytokines. Using the RNase protection assay and ELISA, we quantified expression of chemokines and chemokine receptors in the spinal cord (SC), brain, and lymph nodes of BV8S2 transgenic mice that developed or were protected from EAE by vaccination with BV8S2 protein. In paralyzed control mice, the SC had increased cellular infiltration and strong expression of the chemokines RANTES, IFN-inducible 10-kDa protein, and monocyte chemoattractant protein-1 and the cognate chemokine receptors CCR1, CCR2, and CCR5, with lower expression of macrophage-inflammatory protein (MIP)-1α, MIP-1β, and MIP-2; whereas brain had less infiltration and a lower expression of a different pattern of chemokines and receptors. In TCR-protected mice, there was a decrease in the number of inflammatory cells in both SC and brain. In SC, the reduced cellular infiltrate afforded by TCR vaccination was commensurate with profoundly reduced expression of chemokines and their cognate chemokine receptors. In brain, however, TCR vaccination did not produce significant changes in chemokine expression but resulted in an increased expression of CCR3 and CCR4 usually associated with Th2 cells. In contrast to CNS, lymph nodes of protected mice had a significant increase in expression of MIP-2 and MIP-1β but no change in expression of chemokine receptors. These results demonstrate that TCR vaccination results in selective reduction of inflammatory chemokines and chemokine receptors in SC, the target organ most affected during EAE.

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“…Several investigations have suggested the induction of TCRpeptide-reactive T cells following vaccination with pathogenic T cell lines, clones or peptides derived from the TCR expressed on pathogenic T cells (11, 14 -20). Importantly, the Fr3 region of the TCR V␤8.2 chain has been shown to contain an immunodominant determinant in mouse, rat and human models (11,12,(21)(22)(23)(24). Furthermore, the T cell repertoire reactive to this region cannot be tolerized by neonatal or i.v.…”

mentioning

confidence: 99%

“…Furthermore, the T cell repertoire reactive to this region cannot be tolerized by neonatal or i.v. tolerance-inducing protocols in either mice or rats (11,13,23). We and others have used different approaches to induce efficient expansion of TCR-peptide-reactive regulatory T cells in the hope of identifying the optimal protocol for the modulation of autoimmunity.…”

mentioning

confidence: 99%

Immunodominance in the TCR Repertoire of αTCR Peptide-Specific CD4+ Treg Population That Controls Experimental Autoimmune Encephalomyelitis

Madakamutil

Maricic

Sercarz

et al. 2008

The Journal of Immunology

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Immunodominance in self-Ag-reactive pathogenic CD4+ T cells has been well established in several experimental models. Although it is clear that regulatory lymphocytes (Treg) play a crucial role in the control of autoreactive cells, it is still not clear whether immunodominant CD4+ Treg clones are also involved in control of autoreactivity. We have shown that TCR-peptide-reactive CD4+ and CD8+ Treg play an important role in the spontaneous recovery and resistance from reinduction of experimental autoimmune encephalomyelitis in B10.PL mice. We report, by sequencing of the TCR α- and β-chain associated with CD4+ Treg, that the TCR repertoire is limited and the majority of CD4+ Treg use the TCR Vβ14 and Vα4 gene segments. Interestingly, sequencing and spectratyping data of cloned and polyclonal Treg populations revealed that a dominant public CD4+ Treg clonotype expressing Vβ14-Jβ1.2 with a CDR3 length of 7 aa exists in the naive peripheral repertoire and is expanded during the course of recovery from experimental autoimmune encephalomyelitis. Furthermore, a higher frequency of CD4+ Treg clones in the naive repertoire correlates with less severity and more rapid spontaneous recovery from disease in parental B10.PL or PL/J and (B10.PL × PL/J)F1 mice. These findings suggest that unlike the Ag-nonspecific, diverse TCR repertoire among the CD25+CD4+ Treg population, TCR-peptide-reactive CD4+ Treg involved in negative feedback regulation of autoimmunity use a highly limited TCR V-gene repertoire. Thus, a selective set of immunodominant Treg as well as pathogenic T cell clones can be targeted for potential intervention in autoimmune disease conditions.

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Neonatal injection of Lewis rats with recombinant Vβ8.2 induces T cell but not B cell tolerance and increased severity of experimental autoimmune encephalomyelitis

Cited by 18 publications

References 20 publications

Homeostatic control of immunity by TCR peptide–specific Tregs

Homeostatic control of immunity by TCR peptide–specific Tregs

Reduced Chemokine and Chemokine Receptor Expression in Spinal Cords of TCR BV8S2 Transgenic Mice Protected Against Experimental Autoimmune Encephalomyelitis with BV8S2 Protein

Immunodominance in the TCR Repertoire of αTCR Peptide-Specific CD4+ Treg Population That Controls Experimental Autoimmune Encephalomyelitis

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