Role of Bim in regulating CD8+ T-cell responses during chronic viral infection
Role of Bim in regulating CD8+ T-cell responses during chronic viral infection
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DOI：
10.1128/jvi.00855-06
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发表时间：
2006-09-01
影响因子：
5.4
通讯作者：
Hildeman, David
中科院分区：
文献类型：
--
作者：
Grayson, Jason M.;Weant, Ashley E.;Hildeman, David
细胞凋亡对免疫系统的发育和维持至关重要。促凋亡的BCl-2家族成员Bim对正常的免疫系统稳态很重要。尽管先前的实验表明，在急性病毒感染期间，Bim对抗原特异性CD8(+) T细胞的凋亡至关重要，但在慢性病毒感染期间，Bim的作用尚不清楚。利用淋巴细胞性脉络丛脑膜炎病毒克隆13感染小鼠，我们证实了Bim在慢性病毒感染期间CD8+ t细胞凋亡中的作用。通过主要组织相容性复合体I类四聚体染色对抗原特异性CD8(+) T细胞进行计数，发现CD8(+) D(b)NP396-404(+) T细胞在野生型小鼠中广泛缺失，在Bim突变小鼠中几乎没有减少。这与CD8(+)D(b)GP33-41（+）和CD8(+)D(b) GP276-286(+)T细胞在Bim突变型和野生型小鼠中数量减少形成对比。在Bim突变小鼠中，CD8(+) D(b)Np396-404(+) T细胞数量的增加是由于缺乏凋亡，而不能用增殖改变、组织的不同归巢或CD4(+) T细胞的帮助增加来解释。当检测病毒滴度时，最初在两组中都观察到高水平，但在Bim突变小鼠中，脾脏和血清的清除速度略有加快。这些实验证明了Bim在慢性病毒感染过程中下调CD8(+) t细胞反应的关键作用，并对在抗原持续存在的情况下（如慢性感染、自身免疫综合征和癌症）设计优化免疫疗法的策略具有启示意义。
Apoptosis is critical for the development and maintenance of the immune system. The proapoptotic BCl-2 family member Bim is important for normal immune system homeostasis. Although previous experiments have shown that Bim is critical for the apoptosis of antigen-specific CD8(+) T cells during acute viral infection, the role of Bim during chronic viral infection is unclear. Using lymphocytic choriomeningitis virus clone 13 infection of mice, we demonstrate a role for Bim in CD8+ T-cell apoptosis during chronic viral infection. Enumeration of antigen-specific CD8(+) T cells by major histocompatibility complex class I tetramer staining revealed that CD8(+) D(b)NP396-404(+) T cells, which undergo extensive deletion in wild-type mice, exhibited almost no decrease in Bim mutant mice. This contrasts with CD8(+)D(b)GP33-41(+) and CD8(+) D(b)GP276-286(+)T cells that underwent similar decreases in numbers in both Bim mutant and wild-type mice. Increased numbers of CD8(+) D(b)Np396-404(+) T cells in Bim mutant mice were due to lack of apoptosis and could not be explained by altered proliferation, differential homing to tissues, or increased help from CD4(+) T cells. When viral titers were examined, high levels were initially observed in both groups, but in Bim mutant mice, clearance from the spleen and sera was slightly accelerated. These experiments demonstrate the critical role of Bim during chronic viral infection to down-regulate CD8(+) T-cell responses and have implications for designing strategies for optimizing immunotherapies during situations where antigen persists, such as chronic infection, autoimmune syndromes, and cancer.