The Induction and Maintenance of Transplant Tolerance Engages Both Regulatory and Anergic CD4+T cells.
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 coexpressinggranzyme BandTbx21, 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 Foxp3DTRrecipient 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 CD73hiFR4hiphenotype, 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.
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; INSERM U1151, Institut Necker-Enfants Malades, Paris, France; CNRS UMR 8253, Institut Necker-Enfants Malades, Paris, France.
Alix
A
Besançon
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; INSERM U1151, Institut Necker-Enfants Malades, Paris, France; CNRS UMR 8253, Institut Necker-Enfants Malades, Paris, France.
Marije
M
Baas
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; INSERM U1151, Institut Necker-Enfants Malades, Paris, France; CNRS UMR 8253, Institut Necker-Enfants Malades, Paris, France.
Tania
T
Goncalves
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; INSERM U1151, Institut Necker-Enfants Malades, Paris, France; CNRS UMR 8253, Institut Necker-Enfants Malades, Paris, France.
Fabrice
F
Valette
Therapeutic Immunology Group, Sir William Dunn School of Pathology, University of Oxford , Oxford , UK.
Herman
H
Waldmann
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; INSERM U1151, Institut Necker-Enfants Malades, Paris, France; CNRS UMR 8253, Institut Necker-Enfants Malades, Paris, France.
Lucienne
L
Chatenoud
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; INSERM U1151, Institut Necker-Enfants Malades, Paris, France; CNRS UMR 8253, Institut Necker-Enfants Malades, Paris, France.
Sylvaine
S
You
CD3 monoclonal antibody; anergy; immunotherapy; regulatory T cells; transplant tolerance