Motta M, Rassenti L, Shelvin B J, Lerner S, Kipps T J, Keating M J, Wierda W G
Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX 77230-1402, USA.
Leukemia. 2005 Oct;19(10):1788-93. doi: 10.1038/sj.leu.2403907.
Patients with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Since CD152 (CTLA-4) plays a critical role in downregulating T-cell responses, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from treatment-naïve patients with CLL. CD4+ and CD8+ T cells from these patients demonstrated significantly increased sCD152 and cCD152 compared to normal donors. Furthermore, these patients had an increased proportion of the regulatory CD4(+)/CD25(+)/CD152+ subset that correlated with advanced Rai stage, unfavorable cytogenetics and low serum IgG and IgA levels. The expression of sCD152 by T cells also correlated with ZAP-70 expression by CLL B cells. The proportion of CD4(+)/CD25+ cells was also correlated with unmutated immunoglobulin heavy chain variable gene status. Blockade of CD152 with monoclonal antibody (mAb) in proliferation assays was associated with potent T-cell proliferation in response to autologous and allogeneic CD40-activated CLL B cells. In summary, T cells from patients with CLL may be primed for anergy by expressing increased amounts of CD152; anti-CD152 mAb may represent a therapeutic opportunity to enhance an immune response against autologous leukemia cells.
慢性淋巴细胞白血病（CLL）患者存在细胞免疫和体液免疫缺陷。由于CD152（细胞毒性T淋巴细胞相关抗原4）在下调T细胞反应中起关键作用，我们研究了初治CLL患者新鲜分离的T细胞表面和细胞质CD152（分别为sCD152和cCD152）的表达。与正常供体相比，这些患者的CD4+和CD8+T细胞显示sCD152和cCD152显著增加。此外，这些患者调节性CD4(+)/CD25(+)/CD152+亚群比例增加，这与Rai分期晚期、不良细胞遗传学以及低血清IgG和IgA水平相关。T细胞sCD152的表达也与CLL B细胞的ZAP-70表达相关。CD4(+)/CD25+细胞比例也与未突变的免疫球蛋白重链可变基因状态相关。在增殖试验中用单克隆抗体（mAb）阻断CD152与对自体和同种异体CD40激活的CLL B细胞反应中有效的T细胞增殖相关。总之，CLL患者的T细胞可能因表达增加的CD152而处于无反应状态；抗CD152 mAb可能代表增强针对自体白血病细胞免疫反应的治疗机会。
