Author(s):
Agua-Doce, Ana ; Caridade, Marta ; Oliveira, Vanessa G ; Bergman, Lisa ; Lafaille, Maria C ; Lafaille, Juan J ; Demengeot, Jocelyne ; Graca, Luis
Date: 2018
Persistent ID: http://hdl.handle.net/10400.7/843
Origin: ARCA - Access to Research and Communication Annals
Subject(s): Aluminum Hydroxide; Animals; Antibodies; Antigen Presentation; CD4 Antigens; Cell Differentiation; Cells, Cultured; Clonal Selection, Antigen-Mediated; Forkhead Transcription Factors; Interleukin-10; Interleukin-2; Lymphocyte Activation; Mice; Mice, Knockout; Mice, Transgenic; Ovalbumin; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Immune Tolerance; Skin Transplantation
Description
It has been shown that dominant tolerance, namely in transplantation, requires Foxp3+regulatory T cells. Although most tolerance-inducing regimens rely on regulatory T cells, we found that induction of tolerance to proteins in aluminum hydroxide can be achieved in Foxp3-deficient mice using nondepleting anti-CD4 Abs. This type of tolerance is Ag specific, and tolerant mice retain immune competence to respond to unrelated Ags. We demonstrated with chicken OVA-specific TCR-transgenic mice that the same tolerizing protocol (CD4 blockade) and the same target Ag (OVA) achieves Foxp3-dependent transplantation tolerance to OVA-expressing skin grafts, but Foxp3-independent tolerance when the Ag is provided as OVA-aluminum hydroxide. In the latter case, we found that tolerance induction triggered recessive mechanisms leading to elimination of effector cells and, simultaneously, a dominant mechanism associated with the emergence of an anergic and regulatory CTLA-4+IL-2lowFoxp3-T cell population, where the tolerance state is IL-10 dependent. Such Foxp3-independent mechanisms can improve the efficacy of tolerance-inducing protocols.
