A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2.
OX40 stimulation is known to enhance activation of effector T cells and to inhibit induction and suppressive function of Treg. Here we uncovered a novel role of OX40 in sustaining Treg competitive fitness in vivo, during repopulation of lymphopenic hosts and reconstitution of BM chimeras. Defective expansion of OX40-null Treg diminished their ability to suppress inflammation in a model of lymphopenia-driven colitis. OX40-mediated promotion of Treg fitness spanned beyond lymphopenic environments, as endogenous Treg in OX40-null mice showed decreased accumulation during thymic development, enhanced susceptibility to antibody-mediated depletion and defective turnover following thymectomy. In vitro, OX40-deficient Treg were found to be intrinsically hyporesponsive to IL-2, in terms of Stat5 phosphorylation and proliferation, according to elevated SOCS1 content and reduced miR155 expression. Therefore, OX40 is a key factor in shaping Treg sensitivity to IL-2 and promoting their proliferation and survival, toward accurate immune regulation.
Piconese
Silvia
S
Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Pittoni
Paola
P
Burocchi
Alessia
A
Gorzanelli
Andrea
A
Carè
Alessandra
A
Tripodo
Claudio
C
Colombo
Mario P
MP
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology*; D005434:Flow Cytometry; D007376:Interleukin-2 / Q000276:immunology*; D008231:Lymphopenia / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000276:immunology; D011828:Radiation Chimera; D053262:Receptors, OX40 / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D007376:Interleukin-2; D053262:Receptors, OX40; D050799:STAT5 Transcription Factor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C505717:Tnfrsf4 protein, mouse