Baeten Dominique, Louis Stéphanie, Braud Christophe, Braudeau Cécile, Ballet Caroline, Moizant Frédéric, Pallier Annaik, Giral Magali, Brouard Sophie, Soulillou Jean-Paul
Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité 643: "Immunointervention dans les Allo- et Xénotransplantations," and Institut de Transplantation Et de Recherche en Transplantation (ITERT), Nantes, France.
J Am Soc Nephrol. 2006 Jan;17(1):294-304. doi: 10.1681/ASN.2005020178. Epub 2005 Dec 7.
A substantial proportion of long-term kidney graft recipients, including those with a stable renal function in the absence of immunosuppressive therapy, present a skewed T cell receptor (TCR) Vbeta chain usage, essentially in the CD8+ subset. This study analyzed in more detail phenotypical and functional alterations of CD8+ lymphocytes in drug-free tolerant patients (DF-Tol) compared with recipients with chronic rejection (CR). Phenotyping revealed a significant increase in central memory and a decrease in effector CD8+ lymphocytes in DF-Tol versus CR. The expression of CD28+ and CD27+ on these effector cells was significantly decreased in CR. These profiles were stable over time and independent of treatment. Functionally, the CD8+CD28- lymphocytes were less sensitive to apoptosis than their CD8+CD28+ counterparts, without differences in polyclonal proliferation. The CD8+CD28- cells did not express GITR and FoxP3 but were characterized by high levels of preformed perforin and granzyme A, pointing toward a cytotoxic rather than a suppressor function. CD8+CD28- lymphocytes did not show antigen-specific degranulation when co-cultured with targets that bear donor HLA class I antigens, suggesting that the cytotoxicity is directed either to other determinants of the graft or to nongraft epitopes. Of interest, CD8+ cells from DF-Tol displayed the same profile as healthy individuals, indicating an increase in CD8+CD28- effector lymphocytes in CR rather than a decrease in DF-Tol. CD8+ lymphocytes from stable kidney recipients under conventional maintenance immunosuppression displayed a mixed profile, independent of treatment and time of sampling. Taken collectively, these data show a strong cytotoxicity-associated CD8+CD28- signature in CR and suggest a suppression of pathologic cytotoxicity in DF-Tol. Further prospective studies should assess whether serial CD8+ phenotyping may help to identify patients who are at risk for CR when immunosuppression is tapered.
相当一部分长期肾移植受者，包括那些在无免疫抑制治疗情况下肾功能稳定的受者，呈现出T细胞受体（TCR）Vβ链使用偏态，主要在CD8 +亚群中。本研究更详细地分析了与慢性排斥反应（CR）受者相比，无药物耐受患者（DF-Tol）中CD8 +淋巴细胞的表型和功能改变。表型分析显示，与CR相比，DF-Tol中的中枢记忆细胞显著增加，效应CD8 +淋巴细胞减少。CR中这些效应细胞上CD28 +和CD27 +的表达显著降低。这些特征随时间稳定且与治疗无关。在功能上，CD8 + CD28 -淋巴细胞比其CD8 + CD28 +对应细胞对凋亡更不敏感，在多克隆增殖方面无差异。CD8 + CD28 -细胞不表达糖皮质激素诱导的肿瘤坏死因子受体（GITR）和叉头框蛋白3（FoxP3），但特征是高水平的预存穿孔素和颗粒酶A，表明具有细胞毒性而非抑制功能。当与携带供体HLA I类抗原的靶细胞共培养时，CD8 + CD28 -淋巴细胞未显示抗原特异性脱颗粒，这表明细胞毒性要么针对移植物的其他决定簇，要么针对非移植物表位。有趣的是，DF-Tol的CD8 +细胞表现出与健康个体相同的特征，表明CR中CD8 + CD28 -效应淋巴细胞增加，而不是DF-Tol中减少。常规维持免疫抑制下稳定肾移植受者的CD8 +淋巴细胞表现出混合特征，与治疗和采样时间无关。总体而言，这些数据显示CR中存在与细胞毒性相关的强烈CD8 + CD28 -特征，并提示DF-Tol中病理性细胞毒性受到抑制。进一步的前瞻性研究应评估连续CD8 +表型分析是否有助于识别免疫抑制逐渐减少时发生CR风险的患者。
