CD4+ T Cell-Derived IL-21 and Deprivation of CD40 Signaling Favor the In Vivo Development of Granzyme B-Expressing Regulatory B Cells in HIV Patients
CD4+ T Cell-Derived IL-21 and Deprivation of CD40 Signaling Favor the In Vivo Development of Granzyme B-Expressing Regulatory B Cells in HIV Patients
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DOI：
10.4049/jimmunol.1402568
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发表时间：
2015-04-15
影响因子：
4.4
通讯作者：
Jahrsdoerfer, Bernd
中科院分区：
文献类型：
--
作者：
Kaltenmeier, Christof;Gawanbacht, Ali;Jahrsdoerfer, Bernd
IL-21 可诱导浆细胞和调节性 B 细胞。在本文中，我们证明未经治疗的 HIV 患者表现出 IL-21 表达增强的 CD4(+) T 细胞，以及过表达丝氨酸蛋白酶颗粒酶 B 的调节性 B 细胞的体内频率较高。来自 HIV 患者的表达颗粒酶 B 的调节性 B 细胞（GraB 细胞）表现出 CD5、CD43、CD86 和 CD147 表达增加，但不产生 IL-10。其调节活性的主要功能特征是 TCR-zeta 链的直接颗粒酶 B 依赖性降解，导致增殖 T 细胞反应显着降低。尽管 HIV 患者的 Th 细胞以 Nef 依赖性方式分泌 IL-21，但它们几乎不表达 CD40L。当将这种IL-21(+)CD40L(-) Th细胞与B细胞一起培养时，前者直接诱导B细胞分化为GraB细胞。相比之下，向 T 细胞/B 细胞培养物中添加可溶性 CD40L 多聚体可将 B 细胞分化转向浆细胞，表明 CD40L 决定 IL-21 依赖性 B 细胞分化的方向。作为原理证明，我们在由于 NEMO 突变而缺乏完整 CD40 信号传导的患者中证实了这种机制。该患者的大部分外周 B 细胞是 GraB 细胞，并且强烈抑制 T 细胞增殖。总之，GraB 细胞代表了人类中有效的调节性 B 细胞，其表型和功能与 B10 细胞不同，并且出现在早期 HIV 感染中。 GraB 细胞可能对 HIV 患者的免疫功能障碍有重大影响，也可能解释疫苗接种后无效的抗体反应。使用可溶性 CD40L 多聚体可能有助于改善 HIV 患者的疫苗接种反应。
IL-21 can induce both plasma cells and regulatory B cells. In this article, we demonstrate that untreated HIV patients display CD4(+) T cells with enhanced IL-21 expression and high in vivo frequencies of regulatory B cells overexpressing the serine protease granzyme B. Granzyme B-expressing regulatory B cells (GraB cells) cells from HIV patients exhibit increased expression of CD5, CD43, CD86, and CD147 but do not produce IL-10. The main functional characteristic of their regulatory activity is direct granzyme B-dependent degradation of the TCR-zeta-chain, resulting in significantly decreased proliferative T cell responses. Although Th cells from HIV patients secrete IL-21 in a Nef-dependent manner, they barely express CD40L. When culturing such IL-21(+)CD40L(-) Th cells with B cells, the former directly induce B cell differentiation into GraB cells. In contrast, the addition of soluble CD40L multimers to T cell/B cell cultures redirects B cell differentiation toward plasma cells, indicating that CD40L determines the direction of IL-21-dependent B cell differentiation. As proof of principle, we confirmed this mechanism in a patient lacking intact CD40 signaling due to a NEMO mutation. The majority of peripheral B cells from this patient were GraB cells and strongly suppressed T cell proliferation. In conclusion, GraB cells represent potent regulatory B cells in humans that are phenotypically and functionally distinct from B10 cells and occur in early HIV infection. GraB cells may contribute significantly to immune dysfunction in HIV patients, and may also explain ineffective Ab responses after vaccination. The use of soluble CD40L multimers may help to improve vaccination responses in HIV patients.