Javia Luv Ram, Rosenberg Steven A
Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.
J Immunother. 2003 Jan-Feb;26(1):85-93. doi: 10.1097/00002371-200301000-00009.
Murine studies have suggested that a population of CD4+ T cells expressing the alpha chain of the interleukin (IL)-2 receptor (CD25+) are phenotypically anergic in response to T cell receptor stimulation and can suppress the function of CD4+ and CD8+ T cells. Recent studies of peripheral lymphocytes from healthy human volunteers have identified a similar population, although little is known about the presence and activity of these cells in patients with cancer and their possible impact on anticancer immunization strategies. Thus, the authors have undertaken these studies in patients with metastatic melanoma undergoing immunizations with known melanoma antigens. CD4+ CD25+, CD4+ CD25-, and a 1:1 ratio of these isolated T cells were stimulated with soluble anti-CD3 antibody in the presence of irradiated T cell-depleted PBMCs, and proliferation was assessed by measuring [3H]thymidine incorporation. In 13 patients, isolated CD4+CD25+ T cells proliferated 68% (+/- 5.8%) less than separately cultured CD4+ CD25- T cells. Moreover, CD4+ CD25+ T cells suppressed the proliferation of an equal number of cocultured CD4+ CD25+ T cells in 11 of 13 patients by an average of 60% (+/- 4.9%). Suppression was not seen at day three of culture and became apparent at days five through nine. The degree of suppression was proportional to the numbers of CD4+ CD25+ T cells. Addition of high-dose IL-2 reversed the hypoproliferative phenotype of the CD4+ CD25+ T cells and abrogated their suppressive function. These studies demonstrate that anergic and functionally suppressive CD4+ CD25+ T cells exist in patients with melanoma undergoing tumor antigen immunization and thus may play a role in modifying the magnitude of the T cell response to immunization.
小鼠研究表明，表达白细胞介素（IL）-2受体α链的CD4+ T细胞群体（CD25+）在表型上对T细胞受体刺激无反应，并且能够抑制CD4+和CD8+ T细胞的功能。最近对健康人类志愿者外周淋巴细胞的研究也发现了类似的细胞群体，不过对于癌症患者体内这些细胞的存在情况、活性以及它们对抗癌免疫策略可能产生的影响，人们了解甚少。因此，作者对正在接受已知黑色素瘤抗原免疫治疗的转移性黑色素瘤患者进行了这些研究。分离得到的CD4+ CD25+、CD4+ CD25- T细胞以及这两种细胞按1:1比例混合的细胞，在经辐照去除T细胞的外周血单核细胞（PBMC）存在的情况下，用可溶性抗CD3抗体进行刺激，通过测量[3H]胸腺嘧啶核苷掺入量来评估细胞增殖情况。在13名患者中，分离得到的CD4+ CD25+ T细胞的增殖比单独培养的CD4+ CD25- T细胞少68%（±5.8%）。此外，在13名患者中有11名患者的CD4+ CD25+ T细胞抑制了与其共培养的等量CD4+ CD25+ T细胞的增殖，平均抑制率为60%（±4.9%）。在培养第3天时未观察到抑制作用，而在第5天至第9天变得明显。抑制程度与CD4+ CD25+ T细胞的数量成正比。添加高剂量的IL-2可逆转CD4+ CD25+ T细胞的低增殖表型，并消除其抑制功能。这些研究表明，正在接受肿瘤抗原免疫治疗的黑色素瘤患者体内存在无反应且具有功能抑制作用的CD4+ CD25+ T细胞，因此它们可能在调节T细胞对免疫治疗的反应强度方面发挥作用。
