Alix Besançon, Marije Baas, Tania Goncalves, Fabrice Valette, Herman Waldmann, Lucienne Chatenoud, Sylvaine You
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 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 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 Foxp3(DTR) 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-γ responses. In addition, intragraft Treg-deprived CD4(+) T cells lacked proliferative capacities, expressed high levels of the inhibitory receptor PD-1, and exhibited a CD73(hi)FR4(hi) 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.
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 15 May 2017.
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#17,475,714
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#309
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