T‐Cell Reactivity and Tolerance to Mls<sup>a</sup>‐Encoded Antigens

MacDonald, H. Robson; Glasebrook, Andrew L.; Schneider, R; Lees, Rosemary K.; Pircher, Hanspeter; Pedrazzini, Thierry; Kanagawa, Osami; Nicolas, Jean‐François; Howe, Rawleigh; Zinkernagel, Rolf M.; Hengartner, Hans

doi:10.1111/j.1600-065x.1989.tb00004.x

Cited by 79 publications

(72 citation statements)

References 62 publications

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“…Single CD4 + and CD8 + thymocytes were not deleted and were therefore increased in frequency ( Fig. 2A), consistent with previous findings, demonstrating that double positive cells are particularly sensitive to negative selection [2]. In conclusion, the relevant T cell epitope as well as targeting to MHC class II on APC were both required for effective negative selection of double positive thymocytes under these conditions.…”

Section: Half-lives and Absorption Of Troybodiessupporting

confidence: 79%

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Induction of central T cell tolerance: Recombinant antibodies deliver peptides for deletion of antigen-specific CD4+8+ thymocytes

et al. 2005

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In order to prevent or ameliorate autoimmune disease, it would be desirable to induce central tolerance to peripheral self-antigens. We have investigated whether recombinant antibodies (Ab) that deliver T cell epitopes to antigen-presenting cells (APC) in the thymus can be used to induce thymocyte deletion. Troybodies are recombinant Ab with V regions specific for APC surface molecules that have T cell epitopes genetically introduced in their C domains. When MHC class II-specific Troybodies with the k2 315 T cell epitope were injected into k2 315 -specific TCR transgenic mice, a profound deletion of CD4 + 8 + thymocytes was observed. MHC class II-specific Troybodies were 10-100-fold more efficient than non-targeting peptide Ab, and 500-fold more efficient than synthetic peptide at inducing deletion. Similar findings were observed when MHC class II-specific Troybodies with the OVA 323-339 T cell epitope were injected into OVA-specific TCR transgenic mice. Although deletion was transient after a single injection, newborn mice repeatedly injected with MHC class II-specific Troybodies for 4 weeks, had reduced antigen-specific T cells in peripheral lymphoid tissues and reduced T cell responses. These experiments suggest that Troybodies constructed to target specifically thymic APC could be useful tools for induction and maintenance of central T cell tolerance in autoimmune diseases.

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Section: Half-lives and Absorption Of Troybodiessupporting

confidence: 79%

“…A major mechanism for T cell tolerance is central tolerance, where thymocytes with self-reactivities are clonally deleted by apoptosis in the thymus [1][2][3][4]. As a fail-safe mechanism, T cells that escape central tolerance induction can be tolerized in the periphery by a variety of mechanisms [5,6].…”

Section: Introductionmentioning

confidence: 99%

Induction of central T cell tolerance: Recombinant antibodies deliver peptides for deletion of antigen-specific CD4+8+ thymocytes

et al. 2005

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“…Although it is known that the expressed TCR V␤ repertoire is modified during both positive (32, 35) and negative (33,34,36) thymic selection, the contribution of other factors (such as rearrangement frequency and probability of pairing with pT␣) to TCR V␤ repertoire formation has not been previously evaluated. Our data indicate that the TCR V␤ repertoire is already significantly skewed at the earliest stage of adult thymus development in which VDJ␤ rearrangements can be detected.…”

Section: Discussionmentioning

confidence: 99%

“…It was therefore of interest to determine whether biases in V␤ usage, which are pronounced after positive and negative thymic selection (32)(33)(34)(35)(36), could already be detected at the DN3 stage. Fig.…”

Section: Biased V␤ Repertoire In Dn3 Thymocytesmentioning

confidence: 99%

Biased Vβ Usage in Immature Thymocytes Is Independent of DJβ Proximity and pTα Pairing

Wilson

Maréchal

MacDonald

2001

The Journal of Immunology

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During thymus development, the TCR β locus rearranges before the TCR α locus. Pairing of productively rearranged TCR β-chains with an invariant pTα chain leads to the formation of a pre-TCR and subsequent expansion of immature pre-T cells. Essentially nothing is known about the TCR Vβ repertoire in pre-T cells before or after the expression of a pre-TCR. Using intracellular staining, we show here that the TCR Vβ repertoire is significantly biased at the earliest developmental stage in which VDJβ rearrangement has occurred. Moreover (and in contrast to the VH repertoire in immature B cells), Vβ repertoire biases in immature T cells do not reflect proximity of Vβ gene segments to the DJβ cluster, nor do they depend upon preferential Vβ pairing with the pTα chain. We conclude that V gene repertoires in developing T and B cells are controlled by partially distinct mechanisms.

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“…Mature donor-reactive recipient T cells have been shown to undergo apoptosis soon after BMT under costimulation blockade [8,58]. Clonal deletion has mostly been assessed by following the frequency of T cells/thymocytes expressing certain Vβ subunits on their TCR [8,59]; this is done in donor-recipient strain combinations in which the presentation of endogenous retroviral superantigens requires donor MHC class II (e.g., Vβ5-and Vβ11-positive T cells recognize superantigen presented by donor I-E in the Balb/c to B6 combination). In selected murine studies, peripheral deletion of truly alloreactive CD4 + and CD8 + T cells was directly measured by following syngeneic T cells expressing a transgenic TCR for donor MHC class II or class I, respectively, which were adoptively transferred into the recipient before BMT with costimulation blockade [12,60].…”

Section: Central and Peripheral Clonal Deletionmentioning

confidence: 99%

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

et al. 2015

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Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans.Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells. Keywords: Clonal deletion Mixed chimerism Nonmyeloablative conditioning Transplantation tolerance Treg cells IntroductionLong-term outcome after organ transplantation has improved little in the past few decades and remains suboptimal [1]. Grafts are still lost to immunological damage that is not prevented by current immunosuppressive drug regimens [2], which in addition cause severe adverse effects, including increased risks of malignancy and infection. Therefore, immunological tolerance -i.e., a state of specific nonresponsiveness to donor antigens -remains the "Holy Grail" in clinical organ transplantation. Among the Correspondence: Dr. Thomas Wekerle e-mail: Thomas.Wekerle@meduniwien.ac.at numerous strategies that have been tested over time, chimerismbased tolerance induction appears particularly promising [3,4]. This concept is based on the cotransplantation of donor hematopoietic stem cells (HSCs) (contained in bone marrow (BM) or mobilized peripheral blood stem cells (mPBSCs)) into the organ transplant recipient who has been sufficiently preconditioned, either with radiation or cytotoxic drugs, to permit HSC engraftment. If engraftment is achieved, multilineage chimerism ensues, which is termed "mixed" chimerism if donor representation is clearly detectable (by flow cytometry, for instance) but is less than 100% (which would constitute "full" chimerism) and can be achieved with less extensive recipient conditioning.In 1945 Ray Owen described a naturally occur...

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T‐Cell Reactivity and Tolerance to Mls^a‐Encoded Antigens

Cited by 79 publications

References 62 publications

Induction of central T cell tolerance: Recombinant antibodies deliver peptides for deletion of antigen-specific CD4+8+ thymocytes

Induction of central T cell tolerance: Recombinant antibodies deliver peptides for deletion of antigen-specific CD4+8+ thymocytes

Biased Vβ Usage in Immature Thymocytes Is Independent of DJβ Proximity and pTα Pairing

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

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T‐Cell Reactivity and Tolerance to Mlsa‐Encoded Antigens

Cited by 79 publications

References 62 publications

Induction of central T cell tolerance: Recombinant antibodies deliver peptides for deletion of antigen-specific CD4+8+ thymocytes

Induction of central T cell tolerance: Recombinant antibodies deliver peptides for deletion of antigen-specific CD4+8+ thymocytes

Biased Vβ Usage in Immature Thymocytes Is Independent of DJβ Proximity and pTα Pairing

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

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T‐Cell Reactivity and Tolerance to Mls^a‐Encoded Antigens