Tumor emergence is sensed by self-specific CD44hi memory Tregs that create a dominant tolerogenic environment for tumors in mice.
Early responses of Tregs and effector T cells (Teffs) to their first encounter with tumor cells have been poorly characterized. Here we have shown, in both implanted and in situ-induced mouse tumor models, that the appearance of tumor cells is immediately sensed by CD44hi memory Tregs that are specific for self antigens. The rapid response of these Tregs preceded and prevented activation of naive antitumor Teffs. The relative speed of the Treg versus the Teff response within the first 2-4 days determined the outcome of the antitumor immune response: tolerance or rejection. If antitumor memory Teffs were present at the time of tumor emergence, both Tregs and Teffs were recruited and activated with memory kinetics; however, the Tregs were unable to control the Teffs, which eradicated the tumor cells. This balance between effector and regulatory responses did not depend on the number of Tregs and Teffs, but rather on their memory status. Thus, in the natural setting, dominant tolerogenic immunosurveillance by self-specific memory Tregs protects tumors, just as it protects normal tissues. More generally, our results reveal that the timing of Treg and Teff engagement, determined by their memory status, is an important mode of regulation of immune responses.
Darrasse-Jèze
Guillaume
G
UPMC Univ Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), Paris, France.
Bergot
Anne-Sophie
AS
Durgeau
Aurélie
A
Billiard
Fabienne
F
Salomon
Benoît L
BL
Cohen
José L
JL
Bellier
Bertrand
B
Podsypanina
Katrina
K
Klatzmann
David
D
D019264:Adoptive Transfer; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007156:Immunologic Memory; D008325:Mammary Neoplasms, Experimental / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology; D008654:Mesothelioma / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D018448:Models, Immunological; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009857:Oncogenes; D017634:Self Tolerance; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology*; D013997:Time Factors
D000952:Antigens, Polyomavirus Transforming; C476399:Cd44 protein, mouse; D018076:DNA, Complementary; D018960:Hyaluronan Receptors