STAT1 調控胸腺依賴性與胸腺非依賴性抗原引發 B 淋巴球之分化

Abstract

干擾素 (包含第一型和第二型干擾素)是一種能夠調控先天性和適應性免疫反應的多功能的細胞激素。STAT1是第一型和第二型干擾素共同的訊息傳遞因子。然而，STAT1在抗體反應中扮演的角色目前尚不明確。本論文中，我們證明STAT1正向調控胸腺依賴性與胸腺非依賴性抗原引發的IgG反應，而且此反應是和B淋巴球和T淋巴球的作用有關。此外，STAT1也正向調控IL-4加上CD40抗體以及TLR誘導的IgM反應，而且這個作用在MZ B比FO B顯著。我們進一步發現，STAT1調控TLR誘導的IgM反應是和干擾素的作用無關。Stat1基因剔除的MZ B在受TLR配體刺激後的活化狀態、分裂能力和細胞凋亡的能力並沒有受到影響，但分化成漿細胞和產生IgM的能力則有缺失。有趣的是，我們發現STAT1能和Prdm1(BLIMP-1蛋白的基因名)的啟動子(promoter)結合，進而調控Prdm1 RNA的表現量。而且在經過TLR配體刺激後的Prdm1 RNA表現量在Stat1基因剔除MZ B確實減少。在Stat1基因剔除的MZ B中提高BLIMP-1表現，可以恢復TLR誘導IgM到正常的表現量。TLR誘導Prdm1基因減少的現象，除了Stat1基因剔除的MZ B之外，在脾臟B-1a細胞也可以觀察到。此外，我們發現Stat1基因剔除小鼠對於肺炎鏈球菌的感染比較敏感。靜脈注射肺炎鏈球菌感染後的野生型小鼠的血清，可以保護Stat1基因剔除小鼠免於肺炎鏈球菌感染造成的死亡。我們也證明Stat1基因剔除小鼠對肺炎鏈球菌感染較敏感確實是因為該小鼠MZ B缺少STAT1的緣故。總而言之，我們的實驗結果證明STAT1對於胸腺依賴性和胸腺非依賴性抗原誘導B淋巴球的分化、IgM和IgG的產生扮演著重要的角色。

Interferon (IFN), including type I and II IFNs, are pleiotropic cytokines that modulate the innate and adaptive immunity. STAT1 is a shared signaling mediator of type I and II IFNs. However, the role of STAT1 in antibody responses remains elusive. Here, we demonstrate that STAT1 positively regulates IgG responses in a B cell- and T cell-dependent manner in response to both thymus-dependent (TD) and thymus-independent (TI) antigens. Moreover, STAT1 also positively regulates IL-4 and anti-CD40 antibody- or TLR-mediated IgM responses of B cells which is more prominent in marginal zone B (MZ B) than follicular B (FO B) cells. Further, the STAT1-mediated IgM response of MZ B cells upon TLR stimulation is IFN-independent. While activation, proliferation and apoptosis are not affected, both differentiation into plasma cells and IgM production are impaired in Stat1-/-MZ B cells. Interestingly, STAT1 directly regulates the expression of Prdm1 (encodes BLIMP-1) by binding to its promoter, and Prdm1 expression is reduced in Stat1-/- MZ B cells. Restoration of BLIMP-1 to cells rescues TLR- induced IgM response. The attenuated Prdm1 expression in response to TLR is observed not only in Stat1-/- MZ B cells but also in Stat1-/- splenic B-1a cells. Moreover, Stat1-/- mice are more susceptible to S. pneumoniae infection, which can be rescued by the serum of bacteria primed WT mice. The increased susceptibility to S. pneumoniae infection in Stat1-/- mice is also intrinsic to STAT1 requirement in MZ B cells. Collectively, these results reveal a role of STAT1 in B cell differentiation, and IgM and IgG response to TD and TI antigens.