Foxp3 expressing CD4+CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells

被引:572
作者
Viguier, M
Lemaître, F
Verola, O
Cho, MS
Gorochov, G
Dubertret, L
Bachelez, H
Kourilsky, P
Ferradini, L
机构
[1] Inst Pasteur, INSERM, U277, Unite Biol Mol Gene, F-75724 Paris 15, France
[2] Hop La Pitie Salpetriere, INSERM, U543, Ctr Etud & Rech Virol & Immunol, Paris, France
[3] Hop St Louis, Dept Pathol, Paris, France
[4] Hop St Louis, Assistance Publ Hop Paris, Skin Res Inst, INSERM U532, Paris, France
[5] Hop St Louis, Assistance Publ Hop Paris, Dept Dermatol, Paris, France
关键词
D O I
10.4049/jimmunol.173.2.1444
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Dominant tolerance is mediated by regulatory T cells (T-reg) that control harmful autoimmune T cells in the periphery. In this study, we investigate the implication of T-reg in modulating infiltrating T lymphocytes in human metastatic melanoma. We found that CD4(+)CD25(high) T cells are overrepresented in metastatic lymph nodes (LNs) with a 2-fold increased frequency compared with both tumor-free LNs and autologous PBMCs. These cells express the Foxp3 transcription factor, display an activated phenotype, and display a polyclonal TCR Vbeta chain repertoire. They inhibit in vitro the proliferation and cytokine production of infiltrating CD4(+)CD25(-) and CD8(+) T cells (IL-2, IFN-gamma) through a cell-contact-dependent mechanism, thus behaving as T-reg. In some cases, the presence of T-reg type 1/Th3-like lymphocytes could also be demonstrated. Thus, T-reg are a major component of the immunosuppressive microenvironment of metastatic melanoma LNs. This could explain the poor clinical response of cancer patients under immunotherapeutic protocols, and provides a new basis for future immunotherapeutic strategies counteracting in vivo T-reg to reinforce local antitumor immune responses.
引用
收藏
页码:1444 / 1453
页数:10
相关论文
共 67 条
[1]   Phenotype, localization, and mechanism of suppression of CD4+CD25+ human thymocytes [J].
Annunziato, F ;
Cosmi, L ;
Liotta, F ;
Lazzeri, E ;
Manetti, R ;
Vanini, V ;
Romagnani, P ;
Maggi, E ;
Romagnani, S .
JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 196 (03) :379-387
[2]   Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation [J].
Asano, M ;
Toda, M ;
Sakaguchi, N ;
Sakaguchi, S .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 184 (02) :387-396
[3]   CD4+CD25high regulatory cells in human peripheral blood [J].
Baecher-Allan, C ;
Brown, JA ;
Freeman, GJ ;
Hafler, DA .
JOURNAL OF IMMUNOLOGY, 2001, 167 (03) :1245-1253
[4]   Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma [J].
Balch, CM ;
Buzaid, AC ;
Soong, SJ ;
Atkins, MB ;
Cascinelli, N ;
Coit, DG ;
Fleming, ID ;
Gershenwald, JE ;
Houghton, A ;
Kirkwood, JM ;
McMasters, KM ;
Mihm, MF ;
Morton, DL ;
Reintgen, DS ;
Ross, MI ;
Sober, A ;
Thompson, JA ;
Thompson, JF .
JOURNAL OF CLINICAL ONCOLOGY, 2001, 19 (16) :3635-3648
[5]  
Banchereau J, 2001, CANCER RES, V61, P6451
[6]   In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines [J].
Barrat, FJ ;
Cua, DJ ;
Boonstra, A ;
Richards, DF ;
Crain, C ;
Savelkoul, HF ;
de Waal-Malefyt, R ;
Coffman, RL ;
Hawrylowicz, CM ;
O'Garra, A .
JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 195 (05) :603-616
[7]   CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity [J].
Belkaid, Y ;
Piccirillo, CA ;
Mendez, S ;
Shevach, EM ;
Sacks, DL .
NATURE, 2002, 420 (6915) :502-507
[8]   Tumor antigens recognized by T cells [J].
Boon, T ;
Coulie, PG ;
VandenEynde, B .
IMMUNOLOGY TODAY, 1997, 18 (06) :267-268
[9]   CCR7 expression and memory T cell diversity in humans [J].
Campbell, JJ ;
Murphy, KE ;
Kunkel, EJ ;
Brightling, CE ;
Soler, D ;
Shen, ZM ;
Boisvert, J ;
Greenberg, HB ;
Vierra, MA ;
Goodman, SB ;
Genovese, MC ;
Wardlaw, AJ ;
Butcher, EC ;
Wu, LJ .
JOURNAL OF IMMUNOLOGY, 2001, 166 (02) :877-884
[10]   ANTIGEN-SELECTED T-CELL RECEPTOR DIVERSITY AND SELF-NONSELF HOMOLOGY [J].
CASANOVA, JL ;
MARYANSKI, JL .
IMMUNOLOGY TODAY, 1993, 14 (08) :391-394