Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI77610.15789/2220-7619-2018-3-263-272REVIEWSОБЗОРЫM CELLS ARE THE IMPORTANT POST IN THE INITIATION OF IMMUNE RESPONSE IN INTESTINEМ-КЛЕТКИ — ОДИН ИЗ ВАЖНЫХ КОМПОНЕНТОВ В ИНИЦИАЦИИ ИММУННОГО ОТВЕТА В КИШЕЧНИКЕBykovA. S.БыковА. С.
Russian Federation

PhD, MD (Medicine), Professor, Department of Microbiology, Virology and Immunology.

103009, Russian Federation, Moscow, Mokhovaya str., 11–10.

Phone: +7 916 494-35-43 (mobile).

д.м.н., профессор кафедры микробиологии, вирусологии и иммунологии.

103009, Россия, Москва, ул. Моховая, 11–10,

Тел.: 8 916 494-35-43 (моб.).

bykov@imail.ruKaraulovA. V.КарауловА. В.
Russian Federation

RAS Full Member, PhD, MD (Medicine), Professor, Head of the Department of Clinical Immunology and Allergology.

Moscow.

академик РАН, д.м.н., профессор, зав. кафедрой клинической иммунологии и аллергологии.

Москва.TsomartovaD. A.ЦомартоваД. А.
Russian Federation

PhD (Medicine), Associate Professor, Department of Histology, Cytology, Embryology. 

Moscow.

к.м.н., доцент кафедры гистологии, цитологии и эмбриологии.

Москва.KartashkinaN. L.КарташкинаН. Л.
Russian Federation

PhD (Medicine), Associate Professor, Department of Histology, Cytology, Embryology.

Moscow.

к.м.н., доцент кафедры гистологии, цитологии и эмбриологии.

Москва.GoriachkinaV. L.ГорячкинаВ. Л.
Russian Federation

PhD (Biology), Associate Professor, Department of Histology, Cytology, Embryology.

Moscow.

к.б.н., доцент кафедры гистологии, цитологии и эмбриологии.

Москва.KuznetsovS. L.КузнецовС. Л.
Russian Federation

PhD, MD (Medicine), Professor, Head of the Department of Histology, Cytology, Embryology.

Moscow.

д.м.н., профессор, зав. кафедрой гистологии, цитологии и эмбриологии.

Москва.StonoginaD. A.СтоногинаД. А.
Russian Federation

5th Year Student.

Moscow.

студентка 5 курса.

Москва.

ChereshnevaYe. V.ЧерешневаЕ. В.
Russian Federation

PhD (Medicine), Associate Professor, Department of Histology, Cytology, Embryology.

Moscow.

к.м.н., старший преподаватель кафедры гистологии, цитологии и эмбриологии.

Москва.First Moscow State Medical University (Sechenov University).ФГБОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова МЗ РФ.04112018832632720111201801112018Copyright ©; 2018, Bykov A.S., Karaulov A.V., Tsomartova D.A., Kartashkina N.L., Goriachkina V.L., Kuznetsov S.L., Stonogina D.A., Chereshneva Y.V.Copyright ©; 2018, Быков А.С., Караулов А.В., Цомартова Д.А., Карташкина Н.Л., Горячкина В.Л., Кузнецов С.Л., Стоногина Д.А., Черешнева Е.В.2018Bykov A.S., Karaulov A.V., Tsomartova D.A., Kartashkina N.L., Goriachkina V.L., Kuznetsov S.L., Stonogina D.A., Chereshneva Y.V.Быков А.С., Караулов А.В., Цомартова Д.А., Карташкина Н.Л., Горячкина В.Л., Кузнецов С.Л., Стоногина Д.А., Черешнева Е.В.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/776

Microfold cells (M cells) are specialized intestinal epithelial cells that initiate mucosal immune responses. These unique phagocytic epithelial cells are specialized for the transfer of a broad range of particulate antigens and microorganisms across the follicle-associated epithelium (FAE) into the gut-associated lymphoid tissue (GALT) by a process termed transcytosis. The molecular basis of antigen uptake by M cells has been gradually identified in the last decade. Active sampling of intestinal antigen initiates regulated immune responses that ensure intestinal homeostasis. The delivery of luminal substances across the intestinal epithelium to the immune system is a critical event in immune surveillance resulting in tolerance to dietary antigens and immunity to pathogens (e.g., bacteria, viruses, and parasites) and their toxins. Several specialized mechanisms transport luminal antigen across the gut epithelium. Discovery of M cell-specific receptors are of great interest, which could act as molecular tags for targeted delivery oral vaccine to M cells. Recent studies demonstrated that M cells utilize several receptors to recognize and transport specific luminal antigens. Vaccination through the mucosal immune system can induce effective systemic immune responses simultaneously with mucosal immunity. How this process is regulated is largely unknown. This review aims to show a new understanding of the factors that influence the development and function of M cells; to show the molecules expressed on M cells which appear to be used as immunosurveillance receptors to sample pathogenic microorganisms in the gut; to note how certain pathogens appear to exploit M cells to inject the host; and, finally, how this knowledge is used to specifically "target" antigens to M cells to attempt to improve the efficacy of mucosal vaccines. Recently, substantial progress has been made in our understanding of the factors that influence the development and function of M cells.

Микроскладчатые клетки (М-клетки) представляют собой специализированные эпителиальные клетки кишечника, которые инициируют мукозальный иммунный ответ. Эти уникальные фагоцитирующие эпителиальные клетки специализированы для передачи широкого спектра антигенных частиц и микроорганизмов через фолликуло-ассоциированный эпителий (FAE) в лимфоидную ткань, ассоциированную с кишечником (GALT) посредством процесса, называемого трансцитозом. Молекулярная основа поглощения антигена М-клетками была постепенно идентифицирована в последнее десятилетие. Активный отбор проб кишечного антигена инициирует регулируемые иммунные ответы, которые обеспечивают гомеостаз кишечника. Доставка люминальных веществ через эпителий кишечника в иммунную систему является критическим событием в иммунологическом надзоре, что приводит к толерантности к пищевым антигенам и иммунитету к патогенам (например, бактерий, вирусов и паразитов) и их токсинам. Несколько специализированных механизмов транспортирует люминальный антигена через кишечный эпителий. Большой интерес представляет открытие M-клеточно-специфических рецепторов, которые могут выступать в качестве молекулярных мишеней для целевой доставки пероральной вакцины в M-клетки. Недавние исследования показали, что М-клетки используют несколько рецепторов для распознавания и переноса специфических люминальных антигенов. Вакцинация через иммунную систему слизистой оболочки может вызывать эффективные системные иммунные ответы одновременно с иммунитетом слизистой оболочки. Этот обзор имеет целью продемонстрировать молекулы, экспрессируемые на М-клетках и используемые в качестве рецепторов иммунологического надзора для отбора патогенных микроорганизмов в кишечнике, отметить как некоторые патогены используют М-клетки для инфицирования хозяина, и, наконец, показать как эти знания используются для специфического «нацеливания» антигенов на М-клетки, чтобы попытаться повысить эффективность мукозальных вакцин. В последнее время был достигнут существенный прогресс в понимании факторов, влияющих на развитие и функционирование М-клеток.

antigenGALTM cellsRANKLtranscytosismucosal immunityvaccinesантигенGALTМ-клеткиRANKLтрансцитозмукозальный иммунитетвакцины1. Быков А.С., Зверев В.В., Пашков Е.П., Караулов А.В., Быков С.А. Медицинская микробиология, вирусология и иммунология. Атлас-руководство. М.: МИА, 2018, 416 с.2. Akashi S., Saitoh S., Wakabayashi Y., Kikuchi T., Takamura N., Nagai Y., Kusumoto Y., Fukase K., Kusumoto S., Adachi Y., Kosugi A., Miyake K. Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14. J. Exp. Med., 2003, vol. 198, no. 7, pp. 1035–1042. doi: 10.1084/jem.200310763. Amerongen H.M., Weltzin R., Farnet C.M., Michetti P., Haseltine W.A., Neutra M.R. Transepithelial transport of HIV by intestinal M cells: a mechanism for transmission of AIDS. J. Acquir. Immune Defic. Syndr., 1991, vol. 4, pp. 760–765.4. Asai T., Morrison S.L. The SRC family tyrosine kinase HCK and the ETS family transcription factors SPIB and EHF regulate transcytosis across a human follicle-associated epithelium model. J. Biol. Chem., 2013, vol. 288, pp. 10395–10405. doi: 10.1074/jbc.M112.4374755. Barker N., van Es J.H., Kuipers J., Kujala P., van den Born M., Cozijnsen M., Haegebarth A., Korving J., Begthel H., Peters P.J., Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 2007, vol. 449, pp. 1003–1007. doi: 10.1038/nature061966. Brandtzaeg P. Gate-keeper function of the intestinal epithelium. Benef. Microbes, 2013, vol. 4, pp. 67–82. doi: 10.3920/BM2012.00247. Chen K., Cerutti A. Vaccination strategies to promote mucosal antibody responses. Immunity. 2010, vol. 33, no. 4. pp. 479–491. doi: 10.1016/j.immuni.2010.09.0138. Chiba S., Nagai T., Hayashi T., Baba Y., Nagai S., Koyasu S. Listerial invasion protein internalin B promotes entry into ileal Peyer’s patches in vivo. Microbiol. Immunol. 2011, vol. 55, no. 2, pp. 123–129. doi: 10.1111/j.1348-0421.2010.00292.x9. Cunningham A.L., Guentzel M.N., Yu J.J., Hung C.Y., Forsthuber T.G., Navara C.S., Yagita H., Williams I.R., Klose K.E., Eaves-Pyles T.D., Arulanandam B.P. M-cells contribute to the entry of an oral vaccine but are not essential for the subsequent induction of protective immunity against Francisella tularensis. PLoS One, 2016, vol. 11, no. 4: e0153402. doi: 10.1371/journal.pone.015340210. De Lau W., Kujala P., Schneeberger K., Middendorp S., Li V.S., Barker N., Martens A., Hofhuis F., DeKoter R.P., Peters P.J., Nieuwenhuis E., Clevers H. Peyer’s patch M cells derive from Lgr5(+) stem cells, require SpiB and are induced by RankL in cultured “organoids”. Mol. Cell. Biol., 2012, vol. 32, no. 18, pp. 3639–3647. doi: 10.1128/MCB.00434-1211. Donaldson D.S, Sehgal A., Rios D, Williams I.R., Mabbott N.A. Increased abundance of M cells in the gut epithelium dramatically enhances oral prion disease susceptibility. PLoS Pathog., 2017, vol. 13, no. 2: e1006222. doi: 10.1371/journal.ppat.100622212. Eugenin E.A., Gaskill P.J., Berman J.W. Tunneling nanotubes (TNT) are induced by HIV-infection of macrophages: a potential mechanism for intercellular HIV trafficking. Cell. Immunol., 2009, vol. 254, no. 2, pp. 142–148. doi: 10.1016/j.cellimm.2008.08.00513. Fujimura Y., Takeda M., Ikai H., Haruma K., Akisada T., Harada T., Sakai T., Ohuchi M. The role of M cells of human nasopharyngeal lymphoid tissue in influenza virus sampling. Virchows Arch., 2004, vol. 444, no. 1, pp. 36–42.14. Gebert A., Pabst R. M cells at locations outside the gut. Semin. Immunol., 1999, vol. 11, no. 3, pp. 165–170. doi: 10.1006/smim.1999.017215. Gonzalez-Hernandez M.B., Liu T., Payne H.C., Stencel-Baerenwald J.E., Ikizler M., Yagita H., Dermody T.S., Williams I.R., Wobus C.E. Efficient norovirus and reovirus replication in the mouse intestine requires microfold (M) cells. J. Virol., 2014, vol. 88, no. 12, pp. 6934–6943. doi: 10.1128/JVI.00204-1416. Gousset K., Schiff E., Langevin C., Marijanovic Z., Caputo A., Browman D.T., Chenouard N., de Chaumont F., Martino A., Enninga J., Olivo-Marin J.C., Männel D., Zurzolo C. Prions hijack tunnelling nanotubes for intercellular spread. Nat. Cell Biol. 2009, vol. 11, no. 3, pp. 328–336. doi: 10.1038/ncb184117. Hase K., Kawano K., Nochi T., Pontes G.S., Fukuda S., Ebisawa M., Kadokura K., Tobe T., Fujimura Y., Kawano S., Yabashi A., Waguri S., Nakato G., Kimura S., Murakami T., Iimura M., Hamura K., Fukuoka S., Lowe A.W., Itoh K., Kiyono H., Ohno H. Uptake through glycoprotein 2 of FimH (+) bacteria by M cells initiates mucosal immune response. Nature, 2009, vol. 462, pp. 226–230. doi: 10.1038/nature0852918. Hase K., Ohshima S., Kawano K., Hashimoto N., Matsumoto K. Distinct gene expression profiles characterize cellular phenotypes of follicle-associated epithelium and M cells. DNA Res., 2005, vol. 12, pp. 127–137.19. Helander A., Silvey K.J., Mantis N.J., Hutchings A.B., Chandran K., Lucas W.T., Nibert M.L., Neutra M.R. The viral σ1 protein and glycoconjugates containing α2-3-linked sialic acid are involved in type I reovirus adherence to M cell apical surfaces. J. Virol., 2003, vol. 77, no. 14, pp. 7964–7977. doi: 10.1128/JVI.77.1420. Kanaja F., Ohno H. The Mechanisms of M-cell Differentiation. Biosci. Microbiota Food Health. 2014, vol. 33, no. 3, pp. 91–97. doi: 10.12938/bmfh.33.9121. Kanaya T., Hase K., Takahashi D., Fukuda S., Hoshino K., Sasaki I., Hemmi H., Knoop K.A., Kumar N., Sato M., Katsuno T., Yokosuka O., Toyooka K., Nakai K., Sakamoto A., Kitahara Y., Jinnohara T., McSorley S.J., Kaisho T., Williams I.R., Ohno H. The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. Nat. Immunol., 2012, vol. 13, no. 8, pp. 729–736. doi: 10.1038/ni.235222. Kim S.H., Jang Y.S. Antigen targeting to M cells for enhancing the efficacy of mucosal vaccines. Exp. Mol. Med., 2014, vol. 46, no. 3, pp. 1–14. doi: 10.1038/emm.2013.16523. Kim S.H., Jang Y.S. The development of mucosal vaccines for both mucosal and systemic immune induction and the roles played by adjuvants. Clin. Exp. Vaccine Res., 2017, vol. 6, pp. 15–21. doi: 10.7774/cevr.2017.6.1.1524. Kim S.H., Jung D.I., Yang I.Y., Kim J., Lee K.Y., Nochi T., Kiyono H., Jang Y.S. M cells expressing the complement C5a receptor are efficient targets for mucosal vaccine delivery. Eur J. Immunol., 2011, vol. 41, no.11, pp. 3219–3229. doi: 10.1002/eji.20114159225. Kim S.H., Lee H.Y., Jang Y.S. Expression of the ATP-gated P2X7 receptor on M cells and its modulating role in the mucosal immune environment. Immune Netw., 2015, vol. 15, no. 1, pp. 44–49. doi: 10.4110/in.2015.15.1.4426. Kishikawa S., Sato S., Kaneto S., Uchino S., Kohsaka S., Nakamura S., Kiyono H. Allograft inflammatory factor 1 is a regulator of transcytosis in M cells. Nat. Commun., 2017, vol. 8: 14509. doi: 10.1038/ncomms1450927. Knoop K.A., Kumar N., Butler B.R., Sakthivel S.K., Taylor R.T., Nochi T., Akiba H., Yagita H., Kiyono H, Williams I.R. RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium. J. Immunol., 2009, vol. 183, no. 9, pp. 5738–5747. doi: 10.4049/jimmunol.090156328. Knoop K.A., McDonald K.G., McCrate S, McDole J.R., Newberry R.D. Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon. Mucosal Immunol., 2015, vol. 8, no. 1, pp. 198–210. doi: 10.1038/mi.2014.5829. Kobayashi A., Donaldson D.S., Erridge C., Kanaya T., Williams I.R., Ohno H., Mahajan A., Mabbott N.A. The functional maturation of M cells is dramatically reduced in the Peyer’s patches of aged mice. Mucosal Immunol., 2013, vol. 6, no.5, pp. 1027–1037. doi: 10.1038/mi.2012.14130. Koga T., McGhee J. R., Kato H., Kato R, Kiyono H., Fujihashi K. Evidence for early aging in the mucosal immune system. J. Immunol., 2000, vol. 165, no. 9, pp. 5352–5359. doi: 10.4049/jimmunol.165.9.535231. Kolawole A.O., Gonzalez-Hernandez M.B., Turula H., Yu C., Elftman M.D., Wobus C.E. Oral norovirus infection is blocked in mice lacking Peyer’s patches and mature M cells. J. Virol., 2016, vol. 90, no. 3, pp. 1499–1506. doi: 10.1128/JVI.02872-1532. Kujala P., Raymond C.R, Romeijn M., Godsave S.F., van Kasteren S.I., Wille H., Prusiner S.B., Mabbott N.A., Peters P.J. Prion uptake in the gut: identification of the first uptake and replication sites. PLoS Pathog., 2011, vol. 7 (12): e1002449. doi: 10.1371/journal.ppat.100244933. Lelouard H., Fallet M., de Bovis B., Meresse S., Gorvel J.P. Peyer’s patch dendritic cells sample antigens by extending dendrites through M cell-specific transcellular pores. Gastroenterology, 2012, vol. 142, pp. 592–601.34. Ling J., Liao H., Clark R., Wong M.S., Lo D.D. Structural constraints for the binding of short peptides to Claudin 4 revealed by surface plasrion resonance. J. Biol. Chem., 2008, vol. 283, no. 45, pp. 30585–30595. doi: 10.1074/jbc.M80354820035. Lo D.D., Ling J., Eckelhoefer A.H. M cell targeting by a Claudin 4 targeting peptide can enhance mucosal IgA responses. BMC Biotechnol., 2012, vol. 12: 7. doi: 10.1186/1472-6750-12-736. Lügering A., Floer M., Westphal S, Maaser C., Spahn T.W., Schmidt M.A., Domschke W., Williams I.R., Kucharzik T. Absence of CCR6 inhibits CD4+ regulatory T-cell development and M-cell formation inside Peyer’s patches. Am. J. Pathol., 2005, vol. 166, no. 6, pp. 1647–1654.37. Mabbott N.A., Donaldson D.S., Ohno H., Williams I.R., Mahajan A. Microfold (M) cells; important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol., 2013, vol. 6, no. 4, pp. 666–677. doi: 10.1038/mi.2013.3038. Mach J., Hshieh T., Hsieh D., Grubbs N., Chervonsky A. Development of intestinal M cells. Immunol. Rev., 2005, vol. 206, pp. 177–189. doi: 10.1111/j.0105-2896.2005.00281.x39. Maharjan S., Sing B., Jiang T., Yoon S.-Y., Li H.-S., Kim G., Gu M.J., Kim S.J., Park O.J., Han S.H., Kang S.K., Yun C.H., Choi Y.J., Cho C.S. Systemic administration of RANKL overcomes the bottleneck or oral vaccine delivery through microfold cells in the ileum. Biomaterials, 2016, vol. 84, pp. 286–300. doi: 10.1016/j.biomaterials.2016.01.04340. Manicassamy S., Pulendran B. Modulation of adaptive immunity with Toll-like receptors. Semin. Immunol., 2009, vol. 21, no. 4, pp. 185–193. doi: 10.1016/j.smim.2009.05.00541. Matsumura T., Sugawara Y., Yutani M., Amatsu S., Yagita H., Kohda T., Fukuoka S., Nakamura Y., Fukuda S., Hase K., Ohno H., Fujinaga Y. Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity. Nat. Commun., 2015, vol. 6: 6255. doi: 10.1038/ncomms725542. McDole J.R., Wheeler L.W., McDonald K.G., Wang B., Konjufca V., Knoop K.A., Newberry R.D., Miller M.J. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature, 2012, vol. 483, no. 7389, pp. 345–349. doi: 10.1038/nature1086343. Miller H., Zhang J., Kuolee R., Patel G.B., Chen W. Intestinal M cells: the fallible sentinels? World J. Gastroenterol., 2007, vol. 13, no. 10, pp. 1477–1486.44. Nagatake T., Fujita H., Minato N., Hamazaki Y. Enteroendocrine cells are specifically marked by cell surface expression of Claudin-4 in mouse small intestine. PLoS ONE, 2014, vol. 9, no. 3: e90638. doi: 10.1371/journal.pone.009063845. Nakato G., Fukuda S., Hase K., Goitsuka R., Cooper M.D., Ohno H. New approach for m-cell-specific molecules by screening comprehensive transcriptome analysis. DNA Res. 2009, vol. 16, no. 4, pp. 227–235. doi: 10.1093/dnares/dsp01346. Nakato G., Hase K., Suzuki M., Kimura M., Ato M., Hanazato M., Tobiume M., Horiuchi M., Atarashi R., Nishida N., Watarai M., Imaoka K., Ohno H. Cutting edge: Brucella abortus exploits a cellular prion protein on intestinal M cells as an invasive receptor. J. Immunol., 2012, vol. 189, no. 4, pp. 1540–1544. doi: 10.4049/jimmunol.110333247. Neutra M.R., Frey A., Kraehenuhl J.P. Epithelial M cells: gateways for mucosal infection and immunization. Cell, 1996, vol. 86, no. 3, pp. 345–348; PMID:8756716; http://dx.doi.org/10.1016/S0092-8674(00)80106-348. Nochi T., Yuki Y., Matsumura A., Mejima M., Terahara K., Kim D.Y., Fukuyama S., Iwatsuki-Horimoto K., Kawaoka Y., Kohda T., Kozaki S., Igarashi O., Kiyono H. A novel M cell-specific carbohydrate-targeted mucosal vaccine effectively induces antigen-specific immune responses. J. Exp. Med. 2007, vol. 204, no. 12, pp. 2789–2796.49. Owen R.L., Jones A.L. Epithelial cell specialization within human Peyer’s patches: an ultrastructural study of intestinal lymphoid follicles. Gastroenterol., 1974, vol. 66, no. 2, pp. 189–203. doi: 10.1016/S0016-5085(74)80102-250. Pabst O., Mowat A.M. Oral tolerance to food protein. Mucosal Immunol., 2012, vol. 5, no. 3, pp. 232–239. doi: 10.1038/mi.201251. Rand J.H., Wu X.X., Lin E.Y., Griffel A., Gialanella P., McKitrick J.C. Annexin A5 binds to lipopolysaccharide and reduces its endotoxin activity. MBio, 2012, vol. 3, no.11, pii: e00292-11. doi: 10.1128/mBio.00292-1152. Ren Z., Gay R., Thomas A., Pae M., Wu D., Logsdon L., Mecsas J., Meydani S.N. Effect of age on susceptibility to Salmonella Typhimurium infection in C57BL/6 mice. J. Med. Microbiol., 2009, vol. 58, pt. 12, pp. 1559–1567. doi: 10.1099/jmm.0.013250-053. Rochereau N., Drocourt D., Perouzel E., Pavot V., Redelinghuys P., Brown G.D. Tiraby G., Roblin X., Verrier B., Genin C., Corthésy B., Paul S. Dectin-1 is essential for reverse transcytosis of glycosylated sIgA-antigen complexes by intestinal M cells. PLoS Biol., 2013, vol. 11, no. 9: e1001658. doi: 10.1371/journal.pbio.100165854. Rouch J.D., Scott A., Lei N.Y., Solorzano-Vargas R.S., Wang J., Hanson E.M., Kobayashi M., Lewis M., Stelzner M.G., Dunn J.C.Y., Eckmann L., Martín M.G. Development of funetional microfold (M) cells from intestinal stem cells in primary human enteroids. PLOS one, 2016, vol. 11, no. 1, pp. 1–16. doi: 10.1371/journal.pone.014821655. Rustom A., Saffrich R., Markovic I., Walther P., Gerdes H.H. Nanotubular highways for intercellular organelle transport. Science, 2004, vol. 303, pp. 1007–1010. doi: 10.1126/science.109313356. Sato S., Kaneto S., Shibata N., Takahashi Y., Okura H., Yuki Y., Kunisawa J., Kiyono H. Transcription factor Spi-B-dependent and -independent pathways for the development of Peyer’s patch M cells. Mucosal Immunol., 2013, vol. 6, no. 4, pp. 838–846. doi: 10.1038/mi.2012.12257. Secott T.E., Lin T.L., Wu C.C. Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein facilitates M-cell targeting and invasion through a fibronectin bridge with host integrins. Infect Immun. 2004, vol. 72, no. 7, pp. 3724–3732. doi: 10.1128/IAI.72.7.3724-3732.200458. Siciński P., Rowiński J., Warchoł J.B., Jarzabek Z., Gut W., Szczygieł B., Bielecki K., Koch G. Poliovirus type 1 enters the human host through intestinal M cells. Gastroenterology, 1990, vol. 98, pp. 56–58.59. Tahoun A., Mahajan S., Paxton E., Malterer G., Donaldson D.S., Wang D., Tan A, Gillespie T.L., O’Shea M., Roe A.J., Shaw D.J., Gally D.L., Lengeling A., Mabbott N.A., Haas J., Mahajan A. Salmonella transforms follicle-associated epithelial cells into M cells to promote intestinal invasion. Cell Host Microbe, 2012, vol. 12, no. 5, pp. 645–656. doi: 10.1016/j.chom.2012.10.00960. Terahara K., Yoshida M., Igarashi O., Nochi T., Pontes G.S., Hase K., Ohno H., Kurokawa S., Mejima M., Takayama N., Yuki Y., Lowe A.W., Kiyono H. Comprehensive gene expression profiling of Peyer’s patch M cells, villous M-like cells, and intestinal epithelial cells. J. Immunol., 2008, vol. 180, no. 12, pp. 7840–7846. doi: 10.4049/jimmunol.180.12.784061. Travassos L.H., Girardin S.E., Philpott D.J., Blanot D., Nahori M.A., Werts C., Boneca I.G. Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep., 2004, vol. 5, no. 10, pp. 1000–1006.62. Verbrugghe P., Kujala P., Waelput W., Peters P.J., Cuvelier C.A. Clusterin in human gut-associated lymphoid tissue, tonsils, and adenoids: localization to M cells and follicular dendritic cells. Histochem Cell Biol., 2008, vol. 129, no. 3, pp. 311–320. doi: 10.1007/s00418-007-0369-463. Wang J., Gusti V., Saraswati A., Lo D.D. Convergent and divergent development among M cell lineages in mouse mucosal epithelium. J. Immunol., 2011, vol. 187, no. 10, pp. 5277–5285. doi: 10.4049/jimmunol.110207764. Wang K.C., Huang C.H., Huang C.J., Fang S.B. Impacts of Salmonella enterica serovar Typhimurium and its speG gene on the transcriptomes of in vitro M cells and Caco-2 cells. PLOS ONE, 2016, vol. 11, no. 4, pp. 1–21. doi: 10.1371/journal.pone.015344465. Wang M., Gao Z., Zhang Z., Pan L., Zhang Y. Roles of M cells in infection and mucosal vaccines. Human Vaccines & Immunother., 2014, vol. 10, no. 12, pp. 3544–3551. doi: 10.4161/hv.3617466. Westphal S., Lugering A, von Wedel J., von Eiff C, Maaser C., Spahn T., Heusipp G., Schmidt M.A., Herbst H., Williams I.R., Domschke W., Kucharzik T. Resistance of chemokine receptor 6-deficient mice to Yersinia enterocolitica infection: evidence on defective M-cell formation in vivo. Am. J. Pathol., 2008, vol. 172, no. 3, pp. 671–680. doi: 10.2353/ajpath.2008.07039367. Wobus C.E. Oral norovirus infection is blocked in mice lacking Peyer’s patches and mature M cells. J. Virol., 2016, vol. 90, no. 3, pp. 1499–1506. doi: 10.1128/JVI.02872-15