title: Cutting edge: Receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells.
abstract: CD4(+)Foxp3(+) regulatory T cells (Treg) are critical regulators of immune homeostasis and self-tolerance. Whereas thymic-derived or natural Treg stably express Foxp3, adaptive or induced Treg (iTreg) generated from peripheral CD4 T cells are susceptible to inflammation-induced reversion to pathogenic effector T cells. Building upon our previous observations that T cell-expressed receptors for C3a (C3aR) and C5a (C5aR) drive Th1 maturation, we tested the impact of C3aR/C5aR signaling on induction and stability of alloreactive iTreg. We observed that genetic deficiency or pharmacological blockade of C3aR/C5aR signaling augments murine and human iTreg generation, stabilizes Foxp3 expression, resists iTreg conversion to IFN-γ/TNF-α-producing efffector T cells, and, as a consequence, limits the clinical expression of graft-versus-host disease. Taken together, the findings highlight the expansive role of complement as a crucial modulator of T cell alloimmunity and demonstrate proof-of-concept that targeting C3a/C3aR and C5a/C5aR interactions could facilitate iTreg-mediated tolerance to alloantigens in humans.
authors.affiliation: Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: William
authors.initials: W
authors.lastname: van der Touw
authors.forename: Paolo
authors.initials: P
authors.lastname: Cravedi
authors.forename: Wing-hong
authors.initials: WH
authors.lastname: Kwan
authors.forename: Estela
authors.initials: E
authors.lastname: Paz-Artal
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D000818:Animals; D015926:Complement C3a / Q000276:immunology*; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D007519:Isoantigens; D044087:Receptor, Anaphylatoxin C5a; D015926:Complement C3a