Tumor emergence is sensed by self-specific CD44hi memory Tregs that create a dominant tolerogenic environment for tumors in mice
Guillaume Darrasse-Jèze, … , Katrina Podsypanina, David Klatzmann
Guillaume Darrasse-Jèze, … , Katrina Podsypanina, David Klatzmann
Published August 3, 2009
Citation Information: J Clin Invest. 2009;119(9):2648-2662. https://doi.org/10.1172/JCI36628.
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Research Article Immunology

Tumor emergence is sensed by self-specific CD44hi memory Tregs that create a dominant tolerogenic environment for tumors in mice

Abstract

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.

Authors

Guillaume Darrasse-Jèze, Anne-Sophie Bergot, Aurélie Durgeau, Fabienne Billiard, Benoît L. Salomon, José L. Cohen, Bertrand Bellier, Katrina Podsypanina, David Klatzmann

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Figure 8

Memory status, rather than number, of antitumor Teffs and Tregs dictates tumor outcome in vivo.

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Memory status, rather than number, of antitumor Teffs and Tregs dictates...
(A) Mice were challenged with AB1-HA tumor cells and were injected with PBS, with 9 × 106 HA-specific CD25– T cells from unmanipulated TCR-HA transgenic mice, or with 9 × 106 HA-specific T cells from TCR-HA mice immunized with HA in IFA 2 months earlier. Mean tumor volumes ± SEM are shown (n = 5 mice per group). (B) Mice were Treg depleted by anti-CD25 Ab treatment and challenged with AB1-HA tumor cells at day 0. Untreated mice developed tumors, whereas treated mice did not. After 30 days, treated cured mice were rechallenged with AB1-HA tumor cells and injected with 5 × 106 in vitro–cultured TCR-HA Tregs. A new group of age-matched mice was also injected with AB1-HA cells as a control (inset). Previously treated mice did not develop tumors, despite the injection of large numbers of specific Tregs. Mean tumor volumes ± SEM are shown (n = 5 mice per group; 3 experiments). (C) Addition of TCR-HA–activated amTeffs was sufficient to reject AB1-HA tumor only when injected between day 0 and day 4. BALB/c mice were injected s.c. with 5 × 105 AB1-HA or AB1 at day 0 and i.v. with PBS, or with 5 × 106TCR-HA T cells from immunized TCR-HA mice at day 0, 2, 4, or 6 (n = 5 per group).