TY - JOUR
T1 - Regulatory T Cells Reversibly Suppress Cytotoxic T Cell Function Independent of Effector Differentiation
AU - Mempel, Thorsten R.
AU - Pittet, Mikael J.
AU - Khazaie, Khashayarsha
AU - Weninger, Wolfgang
AU - Weissleder, Ralph
AU - von Boehmer, Harald
AU - von Andrian, Ulrich H.
N1 - Funding Information:
We thank Drs. Richard Flavell and Leonid Gorelik for dnTGFbRII mice, Dr. Paul Allen for Thy1.1 + BALB/c mice, Dr. Karsten Kretschmer for Thy1.1 + pgk-HA × TCR-HA mice, Andrew Intlekofer and Steve Reiner for assistance with PCR, Antonio Peixoto for advice with PCR, Fay Magnusson, Dina Laznik, and Linda Coulson for assistance, and Sarah Henrickson and Tim Buschman for software programming. T.R.M. is supported by a NIH training grant (T32-HL-066987-04) and M.J.P. by the Human Frontier Science Program Organization (LT00369/2003). This work was supported in part by NIH grants RO-AI-061663, RO1-HL54936, and PO1-HL56949 (to U.H.v.A.); RO1-CA96978 and RO1-CA104547 (to K.K); P50-CA-86355 and R24-CA92782 (to R.W.); and R37 AI53102 (to H.v.B); by the Claudia Adams Barr Program in Cancer Research (to K.K.); and by the Dana Foundation Immuno-Imaging Program (to U.H.v.A.). The authors declare that they have no competing financial interests.
PY - 2006/7
Y1 - 2006/7
N2 - Mechanisms of dominant tolerance have evolved within the mammalian immune system to prevent inappropriate immune responses. CD4+CD25+ regulatory T (Treg) cells have emerged as central constituents of this suppressive activity. By using multiphoton intravital microscopy in lymph nodes (LNs) of anesthetized mice, we have analyzed how cytotoxic T lymphocytes (CTLs) interact with antigen-presenting target cells in the presence or absence of activated Treg cells. Nonregulated CTLs killed their targets at a 6.6-fold faster rate than regulated CTLs. In spite of this compromised effector activity, regulated CTLs exhibited no defect in proliferation, induction of cytotoxic effector molecules and secretory granules, in situ motility, or ability to form antigen-dependent conjugates with target cells. Only granule exocytosis by CTLs was markedly impaired in the presence of Treg cells. This selective form of regulation did not require prolonged contact between CTLs and Treg cells but depended on CTL responsiveness to transforming growth factor-β. CTLs quickly regained full killing capacity in LNs upon selective removal of Treg cells. Thus, Treg cells reversibly suppress CTL-mediated immunity by allowing acquisition of full effector potential but withholding the license to kill.
AB - Mechanisms of dominant tolerance have evolved within the mammalian immune system to prevent inappropriate immune responses. CD4+CD25+ regulatory T (Treg) cells have emerged as central constituents of this suppressive activity. By using multiphoton intravital microscopy in lymph nodes (LNs) of anesthetized mice, we have analyzed how cytotoxic T lymphocytes (CTLs) interact with antigen-presenting target cells in the presence or absence of activated Treg cells. Nonregulated CTLs killed their targets at a 6.6-fold faster rate than regulated CTLs. In spite of this compromised effector activity, regulated CTLs exhibited no defect in proliferation, induction of cytotoxic effector molecules and secretory granules, in situ motility, or ability to form antigen-dependent conjugates with target cells. Only granule exocytosis by CTLs was markedly impaired in the presence of Treg cells. This selective form of regulation did not require prolonged contact between CTLs and Treg cells but depended on CTL responsiveness to transforming growth factor-β. CTLs quickly regained full killing capacity in LNs upon selective removal of Treg cells. Thus, Treg cells reversibly suppress CTL-mediated immunity by allowing acquisition of full effector potential but withholding the license to kill.
KW - CELIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=33745978399&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745978399&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2006.04.015
DO - 10.1016/j.immuni.2006.04.015
M3 - Article
C2 - 16860762
AN - SCOPUS:33745978399
SN - 1074-7613
VL - 25
SP - 129
EP - 141
JO - Immunity
JF - Immunity
IS - 1
ER -