The Role of Follicular CD8+ T Cells in Pathogenesis of AIDS-NHL.

项目总结 艾滋病毒感染与患非霍奇金淋巴瘤(NHL)的风险大大增加有关。 几乎所有的艾滋病相关淋巴瘤(ARL)都起源于B细胞。有两个主要机制被认为是 ARL的发生：1)T细胞受损导致EBV+B细胞免疫调节功能丧失 2)慢性B细胞激活导致DNA修饰事件， 导致癌基因突变/易位。因此，慢性B细胞活化和CD8 T细胞受损 细胞功能是淋巴瘤发生的重要因素。最近，两个不同的组织描述了一个 小鼠LCMV模型中表达CXCR5(CXCL13受体)的CD8+T细胞亚群 慢性病毒感染模型。在这些研究中，这种新的CD8+CXCR5+T细胞群体，也被称为 滤泡CD8(fCD8+)T细胞，表达PD1，并被认为是LCMV特异性的，位于 次级淋巴组织。此外，最近发现fCD8+T细胞存在于肿瘤和 促进B细胞活化。此外，在淋巴瘤中还观察到大量的fCD8+T细胞。 老鼠模型。炎症和免疫激活可能是导致fCD8+积聚的原因 B细胞滤泡中的T细胞，因为在淋巴结中有炎症细胞和CXCL13的积聚 艾滋病毒携带者的数量。由于炎症和微生物移位先于ARL发展，并在 在淋巴肿大中起重要作用，有理由认为炎症和微生物易位可能 在HIV感染中fCD8+T细胞的积聚中起重要作用。FCD8+T细胞也可能在 肿瘤生态位的开发和维护。总之，这让我们假设fCD8+T细胞， 已知在艾滋病毒感染中升高的是由炎症/微生物易位引起的，是 肿瘤生态位，并诱导B细胞活化，有助于淋巴肿大和肿瘤生长，以及B细胞 细胞功能障碍。在这项研究中，我们将通过确定：1)来自HIV阴性的fCD8+T细胞来检验这一假设 和HIV+个体诱导B细胞激活和/或Breg细胞，两者都在ARL诊断之前存在(目标1)，2 免疫激活相关的炎症和/或微生物易位有助于fCD8+的产生 T细胞和如果fCD8+T细胞存在于HIV+患者的肠道相关淋巴组织中， 微生物移位/炎症发生(目标2)，以及3)fCD8+T细胞作为肿瘤的一部分发挥作用 研究ARLS中的微环境，并确定它们可能如何促进肿瘤的发展(目标3)。

PROJECT SUMMARY HIV infection is associated with a greatly increased risk for the development of non-Hodgkin lymphoma (NHL). Nearly all AIDS-related lymphomas (ARL) are of B cell origin. Two major mechanisms are believed to contribute to the genesis of ARL: 1) loss of immunoregulation of EBV+ B cells resulting from impaired T cell function late in the course of HIV disease, and 2) chronic B cell activation leading to DNA-modifying events that contribute to oncogene mutations/translocations. Therefore, both chronic B cell activation and impaired CD8 T cell function are important contributors to lymphomagenesis. Recently, two different groups described a subpopulation of CD8+ T cells that expresses CXCR5 (the receptor for CXCL13) in the LCMV model, a mouse model of chronic viral infection. In these studies, this novel population of CD8+CXCR5+ T cells, also called follicular CD8 (fCD8+) T cells, were shown to express PD1, and were seen to be LCMV-specific and located in secondary lymphoid tissues. Additionally, fCD8+ T cells were recently shown to be present in tumors and to promote B cell activation. Moreover, large numbers of fCD8+ T cells have been observed in a lymphoma mouse model. Inflammation and immune activation may be responsible for driving the accumulation of fCD8+ T cells in the B cell follicles, since there is an accumulation of inflammatory cells and CXCL13 in lymph nodes of HIV+ individuals. Since inflammation and microbial translocation precede ARL development and play an important role in lymphomagenesis, it is reasonable to think that inflammation and microbial translocation may be important in the accumulation of fCD8+ T cells in HIV infection. fCD8+ T cells may also play a role in the development and maintenance of the tumor niche. Together, this had led us to hypothesize that fCD8+ T cells, which are known to be elevated in HIV infection, result from inflammation/microbial translocation, are part of the tumor niche, and induce B cell activation contributing to lymphomagenesis and tumor growth, as well as B cell dysfunction. In this study, we will test this hypothesis by determining if: 1) fCD8+ T cells from HIV-negative and HIV+ individuals induce B cell activation and/or Breg cells, both present prior to ARL diagnosis (aim 1), 2) immune activation-associated inflammation and/or microbial translocation contribute to the generation of fCD8+ T cells and if fCD8+ T cells are present in gut associated lymphoid tissue in HIV+ individuals, the site where microbial translocation/inflammation take place (aim 2), and 3) fCD8+ T cells function as part of the tumor micro-environment in ARLs and defining how they may be contributing to tumor development (aim 3).