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乳酸菌の免疫調節機能に関する研究：Lactococcus lactis JCM 5805の免疫賦活作用とLactobacillus paracasei KW3110のインフラマソーム抑制効果

鈴木 弘章 東北大学

2021.03.03

概要

1. 自然免疫による病原体認識と生体防御機構
「牛の乳搾りに従事する女性たちは天然痘に罹らない」という観察結果から，エドワード・ジェンナーは牛痘を接種することで天然痘を予防できることを発見した (1)．この「二度なし現象」の発見をきっかけとして，同じ病原体と再び遭遇した時に一回目よりも迅速に効率的に反応できる仕組みの解明を中心に免疫学は発展した． 現在では，T 細胞，B 細胞が過去に遭遇した病原体の「記憶」として生体内に長く留まること（「免疫記憶」と呼ばれる）で二度なし現象が生じることがわかっている．この T 細胞，B 細胞を中心とする過去の感染の記憶を使った免疫防御システムは獲得免疫と呼ばれる (2)．獲得免疫が感染した病原体を特異的に見分け応答までに時間を要するのに対し，病原体の持つ特徴的な分子パターンをいち早く感知し，それを排除する仕組みは自然免疫と呼ばれる．自然免疫は病原体の速やかな排除のみならず，病原体由来の分子を T 細胞に提示することで獲得免疫の発動にも寄与する (3)．

自然免疫はマクロファージや樹状細胞といった貪食系の細胞がその中心的役割を担う．これらの細胞はパターン認識受容体（Pattern Recognition Receptors ; PRRs）と呼ばれる受容体を発現し，細菌やウイルスといった病原体の有する特徴的な分子パターン（Pathogen Associated Molecular Patterns ; PAMPs）を認識する． PRRs の代表として Toll 様受容体（Toll-like Receptors ; TLRs）があり，これまでに哺乳類で複数のTLRs ファミリーが同定され，それぞれが異なる分子を認識することが知られている (4)．自然免疫研究の礎を築いた TLRs であるが，その解明にはショウジョウバエを用いた研究が契機となった．ショウジョウバエ胚の背腹軸に沿ったパターン形成に関わる受容体としてクローニングされた

Toll は，発生のみならず感染防御にも重要な役割を果たすことが発見された (5)．その後，哺乳類における TLRs に注目が向けられ，TLR4 がショウジョウバエTollのヒトホモログとして最初に報告され (6)，続いてこの分子がグラム陰性菌の成分であるリポ多糖（lipopolysaccharide ; LPS）を認識することが明らかになった (7,8)．TLR4 以外の TLRs としては，ペプチドグリカンやリポタイコ酸を認識する TLR2 (9)，二本鎖 RNA を認識する TLR3 (10)，一本鎖 RNA を認識する TLR7/8 (11-13)，非メチル化 CpG モチーフを有する DNA を認識する TLR9 が知られて いる (14)．また，TLR が主に細胞膜あるいはエンドソーム膜に発現し病原体を 認識するのに対し，細胞質に侵入した病原体を認識する機構も存在する．例えば， Nucleotide-binding oligomerization domain-containing protein 1，2（NOD1，2）に代表される Nod-like Receptors（NLRs）と呼ばれる細胞質内タンパクは細菌のペプチドグリカン由来分子構造を認識する (15,16)．その他にウイルス由来の二本鎖RNA はRetinoic-acid-inducible protein（I RIG-I）(17) やMelanomadifferentiation associated gene 5（MDA5）(18,19) に，DNA は cyclic GMP-AMP Synthase（cGAS）に認識されることが知られている (20)．

病原体が PRRs によって認識されると下流の細胞内シグナルが活性化し，炎症性サイトカインやインターフェロンが誘導される（Figure 1）．PRRs のうちTLRsシグナルを介在するアダプター分子として MyD88 と TRIF が重要な役割を果たす．例えば，TLR4 はリガンドを認識すると MyD88 を介した経路で NF-κB を核内に移行させ TNF（Tumor Necrosis Factor）-αや IL（Interleukin）-6 といった炎症性サイトカインを誘導する (21)．一方で，TRIF を介した経路では IRF3 のリン酸化を促しIFN-βプロモーターを活性化することでI 型インターフェロンの一種である IFN-βを誘導する(22-24)．このようなシグナルを介して産生された炎症性サイトカインは炎症反応を形成し，各種免疫細胞の活性化を促すことで病原体の排除に寄与する (25)．また，I 型インターフェロンはウイルスの増殖を阻害するタンパクの発現を誘導するなどして強力な抗ウイルス機能を発揮する (26)．

Figure 1. 各種 PRRs と細胞内シグナル伝達経路（Steven G Reed et al., Nature Medicine (2013)19 より引用）

2. 樹状細胞による獲得免疫の始動と plasmacytoid DCs の特徴
自然免疫は上述したサイトカインなどの液性因子の産生の他に獲得免疫の始動にも寄与する．獲得免疫の始動には自然免疫細胞の中でも樹状細胞（Dendtiric Cells ; DCs）がその中心的役割を担う．樹状細胞はマウス脾臓から樹の枝のように突起を伸ばす細胞として同定され (27)，その後の研究で T 細胞の反応性を飛躍的に高める機能を有することが見出された (28,29)．現在では，T 細胞に抗原を提示し獲得免疫を始動する抗原提示細胞（Antigen Presenting Cells ; APCs）として主要な役割を果たすことが知られている．樹状細胞が T 細胞による抗原特異的免疫応答を始動するには主に 3 つのシグナルを介すると考えられている．1つ目が主要組織適合遺伝子複合体（Major Histocompatibility Complex ; MHC）を介した T 細胞への抗原情報の提示である．抗原由来のペプチドは MHC 分子に結合して樹状細胞表面に提示されると，その複合体と結合できる T 細胞受容体（T cell Receptor ; TCR）を有する T 細胞に認識され，抗原特異的免疫応答が始動する．2 つ目が補助刺激分子（co-stimulatory molecules）による T 細胞の活性化である．活性化された樹状細胞は補助刺激分子を細胞表面に発現し，T 細胞は補助刺激分子のシグナルを受け取ることで活性化する．代表的な分子として，樹状細胞表面に提示された CD80/86 は T 細胞表面上の CD28 に結合することで T 細胞の活性化を促進する．3 つ目が樹状細胞より産生されたサイトカインによる T細胞の分化制御である．活性化された樹状細胞はサイトカインを産生するが，そのサイトカインの種類によって T 細胞はそれぞれ異なる機能を有するエフェクターT 細胞（Th1, Th2, Th17 など）に分化する．例えば IL-12 や IFN-γは Th1 に， IL-4 や IL-5 は Th2 に，IL-17 は Th17 に分化させる能力を有する．樹状細胞に発現する TLRs とリガンドの結合は炎症性サイトカインやインターフェロンの発現の他に，補助刺激分子や MHC 分子の発現を誘導することで樹状細胞の成熟と T 細胞の活性化を誘導する．

獲得免疫の始動に大きな役割を果たす樹状細胞であるが，大別すると 2 つのサブセットに分類される．そのうち 1 つが古典的樹状細胞（conventional DCs ; cDCs）であり，もう一方が形質細胞様樹状細胞（plasmacytoid DCs ; pDCs）である．cDCs が T 細胞に抗原を提示する APCs として機能を発揮する一方で，pDCsはヒト末梢血中に存在する大量のインターフェロンを産生する細胞として同定された (30,31)．ほとんどの細胞は I 型インターフェロンを産生する能力を有するが，その産生能力はわずかである．一方，pDCs は I 型インターフェロンの中でも IFN-αを大量に産生し，その他の特徴として TLR7 と TLR9 を高発現することで主にウイルス由来の RNA または DNA を認識する．TLR7 と TLR9 による病原体の認識後，pDCs は MyD88 を介して転写因子 IRF7 を核内に移行させ，IFN- αの転写を促進する（Figure 2）．IRF7 はほとんどの細胞で発現しておらず I 型インターフェロン刺激によってその発現が誘導されるが，pDCs は恒常的に IRF7を発現しており，リガンド刺激に応じて迅速に IFN-αを産生することができる (32,33)．以上の特徴から，pDCs が抗ウイルス免疫において非常に強力な免疫細胞であることが示唆されている．実際，生体から pDCs を除去したマウスに肝炎ウイルスを感染させると IFN-αが産生されず，肝炎が重症化する(34)．また，pDCsにのみIRF7 を発現させたマウスではウイルス感染に対して抵抗性を示すことから，pDCs における IRF7 依存的なシグナルがウイルス感染防御に対して主要な役割を果たすことが示唆される(35)．これら I 型インターフェロン産生を介した免疫制御に加えて，pDCs は獲得免疫を活性化することでも抗ウイルス能を発揮する．pDCs を除去したマウスでは，ウイルス抗原特異的な細胞傷害性 T 細胞の増殖が抑制され (36)，また，抗原特異的免疫応答を司る CD4+ T 細胞の機能も低下する (37)．この pDCs による獲得免疫の活性化は，cDCs と協調して発揮されることが示唆されている (38,39)．また，pDCs によるウイルスの認識にも感染細胞との細胞間相互作用が必要であることがわかっており(40,41)，pDCs は I 型インターフェロン産生細胞としての役割のみならず，他の免疫細胞と相互作用をすることで抗ウイルス免疫を発揮することが示唆されている．

Figure 2. pDCs の自然免疫と獲得免疫に対する役割（ Dana Mitchell et al., Journal of Neuroimmunology (2018) 322 より引用）

3. マクロファージによる炎症反応形成とインフラマソームの関与
樹状細胞同様にマクロファージもまた，自然免疫において重要な役割を果たす．組織の傷害や感染に伴い損傷部位に集まったマクロファージは，一酸化窒素や活性酸素を放出することで感染防御に寄与するとともに，TNF-αや IL-1 とい った炎症メディエーターを産生し他の免疫細胞を感染部位に呼び寄せる (42,43)．マクロファージの活性化とともに放出される一酸化窒素や活性酸素は微生物に とって強力な毒となる一方で，周辺組織にも損傷を与え過剰な炎症を誘発しう る．そのため，マクロファージによる炎症反応は生体内で適切に制御される必要 があり，この制御機構が破綻すると慢性的な炎症を起因とした様々な病態を引 き起こすことがわかっている．例えば，代謝性疾患には脂肪組織中のマクロファ ージが関与することが報告されている．通常状態であれば M2 マクロファージ と呼ばれる組織修復型のマクロファージが恒常性維持に寄与しているが，肥満 などによって炎症型のマクロファージにスイッチし，炎症を惹起することで糖 代謝異常が誘発される(44,45)．

マクロファージが関与する病態の一部に，近年インフラマソームと呼ばれる複合体タンパク質の関与が報告されている．インフラマソームは病原体感染や danger signal と呼ばれる生体内危険因子によって細胞質内で形成される複合体タンパク質で，NLRs または absent in melanoma 2（AIM2）とアダプタータンパクである apoptosis-associated speck-like protein containing caspase recruitment domain（ASC），システインプロテアーゼである caspase-1 によって構成される(46,47)．インフラマソーム活性化の刺激に伴い，NLRs または AIM2 は ASC，pro-caspase- 1 と複合体を形成し，インフラマソーム形成に伴って接近した pro-caspase-1 は互いに自己消化して活性型 caspase-1 を生成する．活性型 caspase-1 は IL-1 ファミリーサイトカインである IL-1βや IL-18 の前駆体を切断して成熟化し，炎症反応を誘導する(48)．これらインフラマソームの中でも最も研究が進んだ分子が NLR family pyrin domain containing protein 3（NLRP3）インフラマソームである（Figure 3）．NLRP3 インフラマソームは様々な刺激によって活性化され，その中には病原体感染，ATP や Nigericin による細胞質内カリウム濃度の低下，尿酸結晶，アルミニウム，シリカの貪食に伴うリソソーム膜の破壊などが挙げられる(49-54)．通常，インフラマソームの活性化は病原体感染から生体を防御する役割を担う一方で，その過剰な活性化は 2 型糖尿病，痛風，関節炎といった炎症を起因とする病態に関与する(55-57)．また，加齢に伴って免疫機能が低下する免疫老化にも関与することが報告されており，その制御機構に注目が集まっている(58,59)．

Figure 3. NLRP3 インフラマソーム活性化機構（Eun-Kyeong Jo et al., Cellular & Molecular Immunology (2016) 13 より引用）

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