期刊
JOURNAL OF IMMUNOTHERAPY
卷 28, 期 2, 页码 120-128出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.cji.0000155049.26787.45
关键词
interleukin-2; T regulatory cell; T helper cell; immunetherapy; melanoma; autoimmunity; IL-2 receptor; interleukin-15
资金
- Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] Funding Source: Medline
CD4(+)CD25(+) T regulatory (T-reg) cells control immunologic tolerance to self-antigens and play a role in suppressing antitumor immune responses, but the mechanism of suppression in vivo remains uncertain. Recently, signaling through the high-affinity interleukin-2 (IL-2) receptor has been shown to be critical for T-reg cell differentiation and survival in vivo. Mice deficient in IL-2 or its receptor (CD25 or CD122) or deficient in downstream signaling molecules, including JAK-3 and STAT-5, do not develop a stable population of T,,g cells and subsequently acquire lymphoproliferative disease and autoimmunity. in vitro, IL-2 is required to expand T-reg cells and to induce their suppressive characteristics. Conversely, IL-2based regimens can activate Cellular antitumor immunity and are the mainstay of immunotherapies directed against melanoma and kidney cancers. Given the seemingly disparate effects of IL-2, the authors discuss the possibility that IL-2 may not be the optimal T-cell growth factor in vivo, but rather an inducer of self-tolerance. The authors propose that other gamma(c)-signaling cytokines, including IL-15, may be alternative choices for the immunotherapy of cancer. genotypes is not cell autonomous but is due to a deficiency in naturally occurring T regulatory (T-reg) cells.(3) It is well established that naturally occurring T-reg Cells control immunologic tolerance to self-antigens and represent 5% to 10% of the CD4(+) T cells in rodents and 5% to 15% in humans.(4-9) T-reg cells constitutively express high levels of the cell surface molecules CD25 (IL-2Ralpha), GITR (glucocorticoidinduced TNF receptor), and CTLA-4. They also express a unique intracellular protein, Foxp3, which acts as a master regulator gene for inducing a T-reg phenotype and lineage. T-reg cells are either abnormally regulated or nonexistent in mice with genotypes that are Il2(-/-), 112ralpha(-/-), 112rbeta(-/-), stat5(-/-), jcik3(-/-) andfbxp3(-/-), which all develop some form of fatal lymphoproliferative disease, suggesting a critical role for IL-2 signaling and Foxp3 in the development of self-tolerance mediated through T-reg cells. (10-13) Interestingly, IL-2 signaling is not related to the expression of Foxp3 in T-reg cells,(14) but Foxp3 can negatively regulate the Il2 gene by blocking an NFAT (nuclear factor of activated T cells) binding site in the IL-2 promoter.(15),(16).
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