COVID-19関連追加(2021915-2

番外編(T型IFNによる一過性の血中リンパ球減少)

I型インターフェロンはリンパ球の再循環を直接制御し,一過性の血中リンパ球減少を引き起こす】

Kamphuis E, et al. Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia. Blood. 2006 Nov 15;108(10):3253-61.

https://doi.org/10.1182/blood-2006-06-027599. Epub 2006 Jul 25.

Abstract

早期ウイルス感染では,しばしばリンパ球減少を伴う.これは,臨床症状が現れるよりもずっと前に,血液中のリンパ球数が一過性に減少することを意味する.我々は,水胞性口内炎ウイルス(VSV)に感染し,Toll様受容体(TLR)アゴニストであるpoly(I:C)およびR-848で処理したマウスのリンパ球減少を調べた.いずれの場合も,リンパ球減少はI型インターフェロン受容体(IFNAR)シグナルに決定的に依存していた.骨髄キメラマウスを用いることで,間質や内皮などの放射線抵抗性細胞(radioresistant cell)を,リンパ球減少を引き起こすI型インターフェロン(IFN-α/β)の標的として除外することができた.その代わりに,adoptive transfer experimentsや、B細胞またはT細胞特異的IFNARを欠失させた条件付き遺伝子標的マウスを用いた研究により,IFN-α/βがリンパ球に直接作用し,リンパ球減少を引き起こすのに必要かつほぼ十分な効果を発揮することが明らかになった.さらに,R-848を投与したところ,TNF-αなどの他のサイトカインもT細胞のリンパ球減少に関与していることがわかった.その分子メカニズムを調べたところ,リンパ球減少は主にGタンパク質共役受容体(GPCR: G protein-coupled receptor)やケモカインに依存しないことがわかった.adhesion assayでは,poly(I:C)処理マウスのB細胞は,VCAM-1ではなくICAM-1への接着が中程度に増加した.以上の結果から,IFN-α/βによるリンパ球への直接的な刺激が,リンパ球の再分布に大きな影響を与えることが明らかになった

 

Figure 1: IFN-α/β plays a critical role in the induction of lymphopenia.

(Ai) BL/6 and IFNAR–/– mice were intravenously infected with 2 × 106 PFU VSV. Blood samples were taken at the indicated time points and stained for CD3ϵ and B220. For FACS analysis, data equivalent to approximately 5 μL blood were acquired. Representative results of 1 of 2 similar experiments are shown. (Aii) Twenty-four hours after VSV inoculation, blood samples were stained for CD69 and B220 and subjected to FACS analysis. Representative data of 1 of 4 animals tested are depicted. (Aiii) Serum samples of mice infected with 2 × 106 PFU VSV were taken at the indicated time points and analyzed for IFN-α by ELISA. Results are expressed as mean ± SD (n = 2). (B) Poly(I:C)– and R-848–induced lymphopenia are dependent on IFNAR signaling. BL/6 and IFNAR–/– mice were intraperitoneally treated with poly(I:C), R-848, or PBS, and blood lymphocyte counts were determined. Representative data from 1 of 2 similar experiments are shown. (C) Poly(I:C) induces IFNAR-dependent up-regulation of CD69 in spleen. Splenocytes of PBS or poly(I:C)–treated mice were stained for CD69 and B220 and subjected to FACS analysis. Representative data of 3 similar experiments are depicted. (Di) IFN-α treatment induces lymphopenia. BL/6 mice were treated subcutaneously with 2 × 105 IU IFN-α or PBS, and blood lymphocyte counts were determined. Results are expressed as mean ± SD for 4 mice per group. (Dii) CD69 expression on B and T cells in splenocyte cultures stimulated with graded concentrations of IFN-β was determined by FACS analysis. (E) Poly(I:C)–induced lymphopenia is reversible. Syngeneic CFSE-labeled splenocytes were adoptively transferred to WT recipients. Mice were given injections of poly(I:C) or PBS, and labeled cells in blood were counted. Results are expressed as mean ± SD (n = 3) and are representative of 2 similar experiments.