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Incomplete clonal deletion as prerequisite for tissue-specific minor antigen tolerization
Nina Pilat, … , Fritz Wrba, Thomas Wekerle
Nina Pilat, … , Fritz Wrba, Thomas Wekerle
Published May 19, 2016
Citation Information: JCI Insight. 2016;1(7):e85911. https://doi.org/10.1172/jci.insight.85911.
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Research Article Immunology Transplantation

Incomplete clonal deletion as prerequisite for tissue-specific minor antigen tolerization

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Abstract

Central clonal deletion has been considered the critical factor responsible for the robust state of tolerance achieved by chimerism-based experimental protocols, but split-tolerance models and the clinical experience are calling this assumption into question. Although clone-size reduction through deletion has been shown to be universally required for achieving allotolerance, it remains undetermined whether it is sufficient by itself. Therapeutic Treg treatment induces chimerism and tolerance in a stringent murine BM transplantation model devoid of myelosuppressive recipient treatment. In contrast to irradiation chimeras, chronic rejection (CR) of skin and heart allografts in Treg chimeras was permanently prevented, even in the absence of complete clonal deletion of donor MHC-reactive T cells. We show that minor histocompatibility antigen mismatches account for CR in irradiation chimeras without global T cell depletion. Furthermore, we show that Treg therapy–induced tolerance prevents CR in a linked suppression–like fashion, which is maintained by active regulatory mechanisms involving recruitment of thymus-derived Tregs to the graft. These data suggest that highly efficient intrathymic and peripheral deletion of donor-reactive T cells for specificities expressed on hematopoietic cells preclude the expansion of donor-specific Tregs and, hence, do not allow for spreading of tolerance to minor specificities that are not expressed by donor BM.

Authors

Nina Pilat, Benedikt Mahr, Lukas Unger, Karin Hock, Christoph Schwarz, Andreas M. Farkas, Ulrike Baranyi, Fritz Wrba, Thomas Wekerle

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Figure 1

Treg treatment replaces irradiation to induce multilineage chimerism and central tolerance.

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Treg treatment replaces irradiation to induce multilineage chimerism and...
Groups of B6 mice were treated with a costimulation blockade–based BMT protocol and grafted with 2 × 107 BALB/c BM cells to induce donor-specific tolerance. BMT recipients were additionally treated with nonmyeloablative (3 Gy, n = 8) irradiation or recipient-derived natural Tregs (nTregs)+ (0-Gy Tregs, n = 6). (A) The majority of recipients in both groups developed permanent multilineage chimerism. Donor (H-2Dd) chimerism among leukocytes of the T cell (CD4+ and CD8+), B cell (CD19+), and myeloid (CD11b/Mac1+) lineage. (B) Deletion of donor-reactive T cells (correlates to Vβ11 and Vβ5 expression) was assessed by flow cytometry of peripheral blood at multiple time points after BMT. (C) Central tolerance was assessed by Vβ expression pattern on intrathymic single-positive (SP) CD4 T cells and (D) the presence of intrathymic chimerism 30 weeks after BMT. Flow cytometric staining verified the engraftment of antigen-presenting donor cells in the thymus and central deletion (30 weeks after BMT). (E) Immunofluorescent staining of frozen thymic sections showed coexpression of CD11c (red) and donor MHC II (I-Ek/d, green). Shown as mean percentage + SD; results are representative of at least 3 independent experiments; ***P < 0.0005, **P < 0.005, *P < 0.05; 2-tailed t test.

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