The genetic basis of negative selection of Tcrb-Vll+ T cells

Tomonari, Kyuhei; Fairchild, Sue

doi:10.1007/bf01719234

Cited by 52 publications

(21 citation statements)

References 20 publications

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“…Naive B10 and B10.BR splenocytes served as controls. The donor strain B10.BR mice express I-E, resulting in the deletion of V␤5.1/2 ϩ and V␤11 ϩ T cells (18,19). As B10 mice do not express I-E, they do not delete these two V␤ subfamilies (19,20).…”

Section: Production Of Donor T Cells Is Critical For Clonal Deletion mentioning

confidence: 99%

“…The donor strain B10.BR mice express I-E, resulting in the deletion of V␤5.1/2 ϩ and V␤11 ϩ T cells (18,19). As B10 mice do not express I-E, they do not delete these two V␤ subfamilies (19,20). Relative expression indicates the percentage of V␤-positive cells within the CD8 ϩ or CD4 ϩ T cell subsets of the host (H2K b ) lymphoid gate in peripheral blood.…”

Section: Production Of Donor T Cells Is Critical For Clonal Deletion mentioning

confidence: 99%

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Production of Donor T Cells Is Critical for Induction of Donor-Specific Tolerance and Maintenance of Chimerism

Chilton

Huang

et al. 2004

The Journal of Immunology

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Nonmyeloablative conditioning has significantly reduced the morbidity associated with bone marrow transplantation. The donor hemopoietic cell lineage(s) responsible for the induction and maintenance of tolerance in nonmyeloablatively conditioned recipients is not defined. In the present studies we evaluated which hemopoietic stem cell-derived components are critical to the induction of tolerance in a total body irradiation-based model. Recipient B10 mice were pretreated with mAbs and transplanted with allogeneic B10.BR bone marrow after conditioning with 100–300 cGy total body irradiation. The proportion of recipients engrafting increased in a dose-dependent fashion. All chimeric recipients exhibited multilineage donor cell production. However, induction of tolerance correlated strictly with early production of donor T cells. The chimeras without donor T cells rejected donor skin grafts and demonstrated strong antidonor reactivity in vitro, while possessing high levels of donor chimerism. These animals lost chimerism within 8 mo. Differentiation into T cells was aborted at a prethymic stage in recipients that did not produce donor T cells. Moreover, donor Ag-driven clonal deletion of recipient T cells occurred only in chimeras with donor T cells. These results demonstrate that donor T cell production is critical in the induction of transplantation tolerance and the maintenance of durable chimerism. In addition, donor T cell production directly correlates with the deletion of potentially alloreactive cells.

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Section: Production Of Donor T Cells Is Critical For Clonal Deletion mentioning

confidence: 99%

Section: Production Of Donor T Cells Is Critical For Clonal Deletion mentioning

confidence: 99%

Production of Donor T Cells Is Critical for Induction of Donor-Specific Tolerance and Maintenance of Chimerism

Chilton

Huang

et al. 2004

The Journal of Immunology

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“…The donor strain B10.A expresses I-E, which is required to present superantigens derived from mammary tumor virus 8 and 9 endogenous retroviruses encoded in the B6/B10 background genome (18 -20). Developing thymocytes whose TCR contain V␤5 and V␤11 subunits, which bind to these superantigens, are deleted in I-E-positive B10.A mice, but not in B6 mice, because they do not express I-E (19,21). The mice that received low-dose TCD mAbs plus MR1 showed profound reductions in the percentage of V␤5 ϩ CD4 PBL (normal B6, 2.56%; normal B10.A, 0.00%) to 0.18 Ϯ 0.13%, and V␤11 ϩ CD4 PBL (normal B6, 5.07%; normal B10.A, 0.00%) to 0.17 Ϯ 0.14% at 8 wk post-BMT.…”

Section: Incompletely Depleting Doses Of Anti-cd4 and Anti-cd8 Mabs Omentioning

confidence: 99%

CD4 T Cell-Mediated Alloresistance to Fully MHC-Mismatched Allogeneic Bone Marrow Engraftment Is Dependent on CD40-CD40 Ligand Interactions, and Lasting T Cell Tolerance Is Induced by Bone Marrow Transplantation with Initial Blockade of this Pathway

Ito

Kurtz

Shaffer

et al. 2001

The Journal of Immunology

108

129

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Costimulatory blockade can be used to promote allogeneic marrow engraftment and tolerance induction, but on its own is not 100% reliable. We sought to determine whether one or the other of the CD4 or CD8 T cell subsets of the recipient was primarily responsible for resistance to allogeneic marrow engraftment in mice receiving costimulatory blockade, and to use this information to develop a more reliable, minimal conditioning regimen for induction of mixed chimerism and transplantation tolerance. We demonstrate that a single anti-CD40 ligand mAb treatment is sufficient to completely overcome CD4 cell-mediated resistance to allogeneic marrow engraftment and rapidly induce CD4 cell tolerance, but does not reliably overcome CD8 CTL-mediated alloresistance. The data suggest that costimulation, which activates alloreactive CTL, is insufficient to activate alloreactive CD4 cells when the CD40 pathway is blocked. The addition of host CD8 T cell depletion to anti-CD40 ligand treatment reliably allows the induction of mixed chimerism and donor-specific skin graft tolerance in 3 Gy-irradiated mice receiving fully MHC-mismatched bone marrow grafts. Thus, despite the existence of multiple costimulatory pathways and pathways of APC activation, our studies demonstrate an absolute dependence on CD40-mediated events for CD4 cell-mediated rejection of allogeneic marrow. Exposure to donor bone marrow allows rapid tolerization of alloreactive CD4 cells when the CD40 pathway is blocked, leading to permanent marrow engraftment and intrathymic tolerization of T cells that develop subsequently.

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“…I-E is necessary to present superantigens encoded by the mammary tumor virus (Mtv)-8 and -9 retroviruses, which are encoded in both the B10.A and B6 genomes. These superantigens bind to thymocytes expressing T-cell receptors (TCRs) containing Vb5 or Vb11, resulting in their deletion during intrathymic development and establishing a hole in the repertoire of I-E + strains, such as B10.A (29-31), but not of I-E -strains, such as B6 (31,32 and Vb11 + T cells, so CD8 + -cell depletion precludes the ability to examine early (week 1) Vb5 + and Vb11 + deletion in the peripheral blood after BMT in mice treated with anti-CD40L and anti-CD8 mAb (23). Such deletion is usually apparent between 2 and 3 weeks post-BMT (24).…”

Section: Resultsmentioning

confidence: 99%

Lack of Role for CsA‐Sensitive or Fas Pathways in the Tolerization of CD4 T Cells Via BMT and Anti‐CD40L

Kurtz

Lie

Griffith

et al. 2003

American Journal of Transplantation

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Anti-CD40L mAb plus bone marrow transplantation (BMT) and recipient CD8 T-cell depletion permits long-term mixed hematopoietic chimerism and systemic donor-specific tolerance to be achieved across full MHC barriers. Initial tolerance is characterized by peripheral deletion of donor-reactive CD4 cells. In regimens using costimulatory blockade without BMT to achieve allograft survival, cyclosporine inhibited graft survival, suggesting that the combination may not be clinically applicable. We assessed the role of cyclosporine-sensitive mechanisms and the mechanisms of T-cell apoptosis involved in the induction of early peripheral CD4 + T-cell tolerance by BMT with anti-CD40L. Neither a short course of cyclosporine (14 days) nor the absence of FAS-mediated activation-induced cell death (AICD) blocked the induction or maintenance of donor-specific tolerance. IL-2 production was not associated with tolerance induction, consistent with the lack of a role for Fas-mediated AICD. Mice in which passive T-cell death was impaired because of constitutive expression of a Bcl-x L transgene did not develop tolerance with this protocol. These data confirm that deletion of donor-reactive T cells is critical for the induction of mixed chimerism and tolerance. However, the mechanisms involved may differ from those involved in costimulatory blockade regimens that do not include BMT.

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The genetic basis of negative selection of Tcrb-Vll+ T cells

Cited by 52 publications

References 20 publications

Production of Donor T Cells Is Critical for Induction of Donor-Specific Tolerance and Maintenance of Chimerism

Production of Donor T Cells Is Critical for Induction of Donor-Specific Tolerance and Maintenance of Chimerism

CD4 T Cell-Mediated Alloresistance to Fully MHC-Mismatched Allogeneic Bone Marrow Engraftment Is Dependent on CD40-CD40 Ligand Interactions, and Lasting T Cell Tolerance Is Induced by Bone Marrow Transplantation with Initial Blockade of this Pathway

Lack of Role for CsA‐Sensitive or Fas Pathways in the Tolerization of CD4 T Cells Via BMT and Anti‐CD40L

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