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The Induction and Maintenance of Transplant Tolerance Engages Both Regulatory and Anergic CD4+ T cells.

ABSTRACT: Therapeutic tolerance to self-antigens or foreign antigens is thought to depend on constant vigilance by Foxp3+ regulatory T cells (Tregs). Previous work using a pancreatic islet allograft model and a short pulse of CD3 antibody therapy has shown that CD8+ T cells become anergic and use TGF? and coinhibitory signaling as their contribution to the tolerance process. Here, we examine the role of CD4+ T cells in tolerization by CD3 antibodies. We show that both Foxp3+ Tregs and CD4+ T cell anergy play a role in the induction of tolerance and its maintenance. Foxp3+ Tregs resisted CD3 antibody-mediated depletion, unlike intragraft Th1 CD4+ lymphocytes coexpressing granzyme B and Tbx21, which were selectively eliminated. Tregs were mandatory for induction of tolerance as their depletion at the time of CD3 antibody therapy or for a short time thereafter, by an antibody to CD25 (PC61), led to graft rejection. Early treatment with CTLA-4 antibody gave the same outcome. In contrast, neither PC61 nor anti-CTLA-4 given late, at day 100 posttransplant, reversed tolerance once established. Ablation of Foxp3 T cells after diphtheria toxin injection in tolerant Foxp3DTR recipient mice provided the same outcome. Alloreactive T cells had been rendered intrinsically unresponsive as total CD4+ or Treg-deprived CD4+ T cells from tolerant recipients were unable to mount donor-specific IFN-? responses. In addition, intragraft Treg-deprived CD4+ T cells lacked proliferative capacities, expressed high levels of the inhibitory receptor PD-1, and exhibited a CD73hiFR4hi phenotype, thus reflecting a state of T cell anergy. We conclude that Tregs play a substantive and critical role in guiding the immune system toward tolerance of the allograft, when induced by CD3 antibody, but are less important for maintenance of the tolerant state, where T cell anergy appears sufficient.

SUBMITTER: Besancon A

PROVIDER: S-EPMC5337867 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The Induction and Maintenance of Transplant Tolerance Engages Both Regulatory and Anergic CD4+ T cells.

Besançon Alix A Baas Marije M Goncalves Tania T Valette Fabrice F Waldmann Herman H Chatenoud Lucienne L You Sylvaine S

Frontiers in immunology 20170306

Therapeutic tolerance to self-antigens or foreign antigens is thought to depend on constant vigilance by Foxp3+ regulatory T cells (Tregs). Previous work using a pancreatic islet allograft model and a short pulse of CD3 antibody therapy has shown that CD8+ T cells become anergic and use TGFβ and coinhibitory signaling as their contribution to the tolerance process. Here, we examine the role of CD4+ T cells in tolerization by CD3 antibodies. We show that both Foxp ...[more]

PMID: 28321218

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Project description:BackgroundMesenchymal stem cells (MSCs) are known for their ability to induce the conversion of conventional T cells (Tconvs) into induced regulatory T cells (iTregs) in specific inflammatory contexts. Stable Foxp3 expression plays a major role in the phenotypic and functional stability of iTregs. However, how MSCs induce stable Foxp3 expression remains unknown.MethodsWe first investigated the role of cell-cell contact and cytokine secretion by bone marrow-derived MSCs (BM-MSCs) on the induction, stability, and suppressive functions of Tregs under various experimental conditions that lead to Foxp3 generation by flow cytometry and ELISA respectively. Second, we studied the effect of MSCs on TRAF6, GRAIL, USP7, STUB1, and UBC13 mRNA expression in CD4+ T cells in correlation with the suppressive function of iTregs by real-time PCR; also, we investigated Foxp3 Treg-specific demethylated region (TSDR) methylation in correlation with Foxp3 stability by the high-resolution melting technique. Third, we studied the effect of ex-vivo-expanded BM-MSCs on the induction of transplant tolerance in a model of fully allogeneic skin transplantation. We further analyzed the cytokine secretion patterns in grafted mice as well as the mRNA expression of ubiquitination genes in CD4+ T cells collected from the spleens of protected mice.ResultsWe found that in-vitro MSC-induced Tregs express high mRNA levels of ubiquitination genes such as TRAF6, GRAIL, and USP7 and low levels of STUB1. Moreover, they have enhanced TSDR demethylation. Infusion of MSCs in a murine model of allogeneic skin transplantation prolonged allograft survival. When CD4+ T cells were harvested from the spleens of grafted mice, we observed that mRNA expression of the Foxp3 gene was elevated. Furthermore, Foxp3 mRNA expression was associated with increased TRAF6, GRAIL, UBC13, and USP7 and decreased STUB1 mRNA levels compared with the levels observed in vitro.ConclusionsOur data suggest a possible ubiquitination mechanism by which MSCs convert Tconvs to suppressive and stable iTregs.

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The Induction and Maintenance of Transplant Tolerance Engages Both Regulatory and Anergic CD4+ T cells.

Publications

The Induction and Maintenance of Transplant Tolerance Engages Both Regulatory and Anergic CD4<sup>+</sup> T cells.

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