Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection

被引:69
作者
Brown, Ian E.
Blank, Christian
Kline, Justin
Kacha, Aalok K.
Gajewski, Thomas F.
机构
[1] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Med, Chicago, IL 60637 USA
关键词
D O I
10.4049/jimmunol.177.7.4521
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Although recent work has suggested that lymphopenia-induced homeostatic proliferation may improve T cell-mediated tumor rejection, there is little direct evidence isolating homeostatic proliferation as an experimental variable, and the mechanism by which improved antitumor immunity occurs via homeostatic proliferation is poorly understood. An adoptive transfer model was developed in which tumor-specitic 2C/RAG2(-/-) TCR transgenic CD8(+) T cells were introduced either into the lymphopenic environment of RAG2(-/-) mice or into P14/RAG2(-/-) mice containing an irrelevant CD8(+) TCR transgenic population. RAG2(-/-), but not P14/RAG2(-/-) recipients supported homeostatic proliferation of transferred T cells as well as tumor rejection. Despite absence of tumor rejection in P14/RAG2(-/-) recipients, 2C cells did become activated, as reflected by USE dilution and CD44 up-regulation. However, these cells showed poor IFN-gamma and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide Ag. To determine whether homeostatic proliferation could uncouple T cell anergy, anergic 2C cells were transferred into RAG(-/-) recipients, which resulted in vigorous homeostatic proliferation, recovery of IL-2 production, and acquisition of the ability to reject tumors. Taken together, our data suggest that a major mechanism by which homeostatic proliferation supports tumor rejection is by maintaining and/or reestablishing T cell responsiveness.
引用
收藏
页码:4521 / 4529
页数:9
相关论文
共 63 条
[1]   Preemptive cellular immunotherapy after T-cell-depleted allogeneic hematopoietic stem cell transplantation [J].
Baron, F ;
Beguin, Y .
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 2002, 8 (07) :351-359
[2]  
Beck C, 2001, MICROSC RES TECHNIQ, V52, P387, DOI 10.1002/1097-0029(20010215)52:4<387::AID-JEMT1023>3.0.CO
[3]  
2-W
[4]   PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells [J].
Blank, C ;
Brown, I ;
Peterson, AC ;
Spiotto, M ;
Iwai, Y ;
Honjo, T ;
Gajewski, TF .
CANCER RESEARCH, 2004, 64 (03) :1140-1145
[5]  
Borrello I, 2000, BLOOD, V95, P3011
[6]   PREVENTION OF T-CELL ANERGY BY SIGNALING THROUGH THE GAMMA(C) CHAIN OF THE IL-2 RECEPTOR [J].
BOUSSIOTIS, VA ;
BARBER, DL ;
NAKARAI, T ;
FREEMAN, GJ ;
GRIBBEN, JG ;
BERNSTEIN, GM ;
DANDREA, AD ;
RITZ, J ;
NADLER, LM .
SCIENCE, 1994, 266 (5187) :1039-1042
[7]   Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells [J].
Cho, BK ;
Rao, VP ;
Ge, Q ;
Eisen, HN ;
Chen, JZ .
JOURNAL OF EXPERIMENTAL MEDICINE, 2000, 192 (04) :549-556
[8]  
Cuenca A, 2003, CANCER RES, V63, P9007
[9]   Restored T-cell activation mechanisms in human tumour-infiltrating lymphocytes from melanomas and colorectal carcinomas after exposure to interleukin-2 [J].
De Paola, F ;
Ridolfi, R ;
Riccobon, A ;
Flamini, E ;
Barzanti, F ;
Granato, AM ;
Mordenti, GL ;
Medri, L ;
Vitali, P ;
Amadori, D .
BRITISH JOURNAL OF CANCER, 2003, 88 (02) :320-326
[10]  
Dudley ME, 2002, SCIENCE, V298, P850, DOI 10.1126/science.1076514