KSHV induces immunoglobulin rearrangements in mature B lymphocytes

Kaposi sarcoma herpesvirus (KSHV/HHV-8) is a B cell tropic human pathogen, which is present in vivo in monotypic immunoglobulin λ (Igλ) light chain but polyclonal B cells. In the current study, we use cell sorting to infect specific B cell lineages from human tonsil specimens in order to examine the immunophenotypic alterations associated with KSHV infection. We describe IL-6 dependent maturation of naïve B lymphocytes in response to KSHV infection and determine that the Igλ monotypic bias of KSHV infection in vivo is due to viral induction of BCR revision. Infection of immunoglobulin κ (Igκ) naïve B cells induces expression of Igλ and isotypic inclusion, with eventual loss of Igκ. We show that this phenotypic shift occurs via re-induction of Rag-mediated V(D)J recombination. These data explain the selective presence of KSHV in Igλ B cells in vivo and provide the first evidence that a human pathogen can manipulate the molecular mechanisms responsible for immunoglobulin diversity.

卡波西肉瘤疱疹病毒（Kaposi sarcoma herpesvirus, KSHV/HHV-8）是一种嗜B细胞的人类病原体，该病毒在体内仅存在于表达单型免疫球蛋白λ（immunoglobulin λ, Igλ）轻链的多克隆B细胞中。本研究中，我们通过细胞分选技术对人类扁桃体标本中的特定B细胞亚群实施感染操作，以探究卡波西肉瘤疱疹病毒感染相关的免疫表型改变。我们发现，卡波西肉瘤疱疹病毒感染可诱导初始B淋巴细胞发生依赖于白细胞介素6（interleukin-6, IL-6）的成熟过程，并明确了体内卡波西肉瘤疱疹病毒感染的Igλ单型偏向性源于病毒诱导的B细胞受体（B cell receptor, BCR）编辑。对免疫球蛋白κ（immunoglobulin κ, Igκ）阳性的初始B细胞进行感染，可诱导Igλ的表达及同型共表达，最终导致Igκ的丢失。我们证实，这一表型转变是通过重新激活重组激活基因（recombination activating gene, Rag）介导的V(D)J重组实现的。上述数据阐明了卡波西肉瘤疱疹病毒在体内Igλ阳性B细胞中选择性存在的机制，并首次提供了人类病原体可调控免疫球蛋白多样性相关分子机制的实验证据。