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Preferential Localization of Effector Memory Cells in Nonlymphoid Tissue
Abstract
Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection.
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“Tissue-resident memory (T RM ) cells are the most recently identified subset of memory T cells, initially characterized as effector memory T cells with a preference for residing in nonlymphoid tissues. 287-289”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [287]
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Farber, D. (2023) · Immunological Reviews · doi:10.1111/imr.13229 · Cited by 1
Locher, V., Park, S., Bunis, D., Makredes, S., Burt, T., Fragiadakis, G., & Halkias, J. (2022) · bioRxiv · doi:10.1101/2022.09.19.508328 · Cited by 1
“70 The majority of T cells in mice and humans alike reside in lymphoid and mucosal 71 tissues, with a heterogeneous distribution of subsets and function across specific sites (11,12).”
BackgroundGlucocorticoid signaling mediates CD8+ T cell memory differentiationPreprint
Tehseen, A., Kumar, D., Sarkar, R., Singh, S., Dubey, A., & Sehrawat, S. (2022) · bioRxiv · doi:10.1101/2022.07.19.500581 · Cited by 1
Limiting the priming dose of a SARS CoV-2 vaccine improves virus-specific immunityPreprint
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Loiseau, C., Traoré, B., Ongoïba, A., Kayentao, K., Doumbo, S., Doumtabé, D., de Sousa, K. P., Brady, J. L., Proietti, C., Crompton, P. D., et al. (2021) · Clinical & Translational Immunology · doi:10.1002/cti2.1265 · Cited by 2
Interleukin-21 reduces Listeria monocytogenes secondary infection via CD8+ effector memory T cells
Gazi, M. Y., Takeda, Y., Nara, H., Araki, A., Nemoto, N., & Asao, H. (2020) · doi:10.21203/rs.3.rs-41839/v1 · Cited by 1
Serendipity: Reflections on Being Mentored by Dr. Peter Doherty
Topham, D. (2020) · Viral immunology · doi:10.1089/vim.2019.0181 · Cited by 1
“David presented the results of experiments he performed infecting mice systemically with Listeria monocytogenes and vesicular stomatitis virus, discovering that effector memory CD8 T cells distributed to all nonlymphoid organs upon recovery from infection (15).”
ResultCD4 + T cells persist for years in the human small intestine and mediate robust T H 1 immunityPreprint
Bartolomé-Casado, R., Landsverk, O. J. B., Chauhan, S. K., Sætre, F., Hagen, K. T., Yaqub, S., Øyen, O. M., Horneland, R., Aandahl, E. M., Aabakken, L., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/863407 · Cited by 1
“Studies of mouse models of infection have shown that CD8+ T cells remain in peripheral tissues long after pathogen clearance (Masopust et al., 2001).”
BackgroundCervicovaginal tissue residence imprints a distinct differentiation program upon memory CD8 T cellsPreprint
Davé, V. A., Ojeda, E. F. C., Mair, F., Erickson, J. R., Davis, A. S. W., Koehne, A. L., Soerens, A. G., Czartoski, J., Teague, C., Potchen, N. B., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/769711 · Cited by 1
“Systemic immunization and infection models are routinely used in mice to generate TRM populations across many body sites (Masopust et al., 2001; Milner et al., 2017; Pope et al., 2001; Reinhardt et al., 2001; Steinert et al., 2015).”
BackgroundRoychoudhury, P., Swan, D. A., Duke, E., Corey, L., Zhu, J., Davé, V. A., Spuhler, L. R., Lund, J. M., Prlic, M., & Schiffer, J. (2019) · bioRxiv · doi:10.1101/610634 · Cited by 1
Editorial: Bone marrow progenitors share their experiences with their offspring
Goodridge, H. S. (2014) · Journal of Leukocyte Biology · doi:10.1189/jlb.0813464 · Cited by 1
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Giunta, B. N., Ruscin, A., Salemi, J., Wolfson, A., Fernandez, F., & Tan, J. (2010) · Ageing Research · doi:10.4081/ar.2010.e5 · Cited by 1
David Masopust: Tracking tapirs, T cells, and other David Masopusts
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RetractedConserved Brain-Associated CD8 + T Cell Programs and Their Regulation by the Brain MicroenvironmentPreprint
Park, K., Sanchez, T., Jeon, S., Schade, P. F., Hildebrand, D. G. C., & Yim, Y. S. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.22.761115
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Wolf, D. M., Moelker, E., Wallace, S. E., Reesman, R. A., Hotchkiss, K. M., Blethen, K. E., Hemmers, S., Pfaller, C. K., Borchers, A. L., Norberg, P. K., et al. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03968-z
“In mice, it has been shown that antigen-specific CD8 and CD4 T cells are found in the bone marrow following systemic viral and bacterial infections, including LCMV, influenza, VSV, and Listeria monocytogenes infection [74, 75, 77, 78].”
Qin, Y., Guo, S., Chen, W., Ji, X., Liu, J., & Zheng, H. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1877664
Kumar, A., & Yung, R. L. (2026) · Immunity & Ageing · doi:10.1186/s12979-026-00582-8
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“A pivotal advance came in 2001, when David Masopust and colleagues demonstrated that pathogen-specific T cells could migrate to diverse tissues (e.g., bone marrow, lung, intestine, and kidney) and persist for months as functional effector memory cells [ 3 ].”
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Topham, D. J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1834618
“…2001, Dr. David Masopust, working with Dr. Leo LeFrancois, demonstrated that after systemic infection with Listeria monocytogenes , speci fi c tetramer-positive CD8 T cells could be detected at elevated frequencies in nearly every tissue sampled, even long after the infection had been cleared (10).”
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“…express CCR7 and CD127 and produce IL-2, whereas effector memory cells are poised for rapid IFN-g production upon antigen restimulation (31 – 34) Since the quality and magnitude of memory T cell response is directly proportional to the magnitude of primary response, a primary infection…”
Pushkarna, M., Zwamel, A. H., Verma, S., Malathi, H., Mustafayeva, M., Kaur, H., Al-Nuaimi, A. M. A., Husseen, B., & Dahghani, M. (2026) · Journal of Applied Genetics · doi:10.1007/s13353-025-01041-8
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“Single cell were obtained from PBMCs and various tissues as described previously 16 .”
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Yang, N., Li, C., Liu, R., Qi, X., & Xing, Q. (2024) · Medicine · doi:10.1097/md.0000000000040254
“[46] In a steady state, it can enter nonlymphoid tissues through circulation, [47] facilitating their recruitment to infection sites for rapid control.”
BackgroundTissue‐resident memory T cells: Harnessing their properties against infection for cancer treatment
Fernandes, J., Veldhoen, M., & Ferreira, C. (2024) · BioEssays · doi:10.1002/bies.202400119
“These findings led to the proposal that some memory T cells do not recirculate through blood but are resident within certain NLTs. [18] The differentiation of mouse effector T cells into T RM cells is not dependent on α V -dependent dendritic cell delivery of TGF-β .”
Psoríase de novo ou exacerbação por inibidores de checkpoint PD‐1
Wan, Z., Huang, J., Ou, X.-J., Lou, S., Wan, J.-J., & Shen, Z. (2024) · Anais Brasileiros de Dermatologia (Versão em Português) · doi:10.1016/j.abdp.2024.02.008
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Farber, D. (2023) · Journal of Immunology · doi:10.4049/jimmunol.2300062
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Lund, J. M. (2022) · Mucosal Immunology · doi:10.1038/s41385-022-00485-z
Nanogap Electrodes and Molecular Electronic Devices
Li, T. (2021) · Nanogap Electrodes · doi:10.1002/9783527659562.ch1
DJ-1 depletion slows down immunoaging in T-cell compartmentsPreprint
Zeng, N., Capelle, C. M., Baron, A., Ciré, S., Léonard, C., Coowar, D., Koseki, H., Westendorf, A., Buer, J., Brenner, D., et al. (2021) · bioRxiv · doi:10.1101/2021.05.21.445139
“This clearer phenotype in blood is in accordance with the notion that Tem are mainly distributed in non-lymphoid tissues (Masopust et al. 2001) and KLRG1 is mainly expressed among CD8 Tem.”
BackgroundTakahashi, D., Wang, Q., Seo, G., Shui, J., Mikulski, Z., Marcovecchio, P., Takahashi, M., Surh, C. D., Cheroutre, H., & Kronenberg, M. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.09.30.317628
“They are tissue resident memory cells derived from antigen-primed conventional or mainstream CD4+ or CD8αβ+ T cells (Lefrancois and Masopust, 2002; Masopust et al., 2001), but have an oligo clonal TCR repertoire (Regnault et al., 1994).”
BackgroundMemory Lymphocyte Clusters in Genital Immunity: Role of Tissue-Resident Memory T Cells (TRM)
Iijima, N. (2020) · Current topics in microbiology and immunology · doi:10.1007/82_2020_213 · Cited by 1
Belz, G. T. (2020) · Viral Immunology · doi:10.1089/vim.2019.0186
“This allowed the development of a much clearer understanding of the dynamic regulation of cells in different tissue compartments, their trafficking behavior, and functional capability within their various niches (48,49,57).”
BackgroundRecent Advances in Lung Immunobiology
Ramonell, R. P., Prasla, Z., Terry, C. R., Schulman, D. A., & Lee, F. E.-H. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2019-0183ro
Mucosal Macrophage Polarization Role in the Immune Modulation
Wu, T., Chen, S., & Wu, Y. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.86609
Mackay, L. K. (2018) · Nature reviews. Immunology · doi:10.1038/s41577-018-0064-9
Expansion of the CD8 memory T cells : implications for the self-renewal gene Hoxb4
Chiang, G., & Gloria, E. (2018) · doi:10.71781/26548
“CD8 Tem cells barely express CD62L or CCR7 or not at all (Masopust et al., 2001).”
Barbarroux, L. (2017) · doi:10.70675/92d7a50dza7d2z4aa1z8f8cz42f7e4835d8f
“Les cellules mémoires ont par exemple été classées en deux catégories principales : les cellules T mémoires centrales CD62L+ (TCM) et les cellules T mémoires effectrices CD62L- (TEM) (Masopust et al. [90], 22 CHAPITRE 1.”
InfluentialRen, J., & Bin, L. I. (2016) · Chinese Science Bulletin (Chinese Version) · doi:10.1360/n972016-00797
Grau, M. (2016) · theses.fr (ABES) · doi:10.70675/2d6ddf6az693bz4096z8988z078b5283dc9a
“Lors d’une restimulation par l’antigène dont ils sont spécifiques, les TEM prolifèrent peu et produisent rapidement de l’IFN-γ et des molécules cytotoxiques (Sallusto et al., 1999; Wherry et al., 2003; Masopust et al., 2001).”
BackgroundImpact of IL-7 signaling on adoptive T cell therapy
Deiser, K. (2016) · edoc Publication server (Humboldt University of Berlin) · doi:10.18452/17419
Ghenassia, A. (2015) · theses.fr (ABES) · doi:10.70675/258b493cz74a9z4788zbbb4za8046cd94fe0
“Les TEM n’expriment pas à leur surface CCR7 et CD62L, sont essentiellement présents dans les tissus (Masopust et al., 2001) et le sang périphériques et sont dotés de différentes fonctions effectrices qui seront détaillées ultérieurement dans ce chapitre (voir Partie 3.). ii.”
BackgroundCD40 Is Required for Protective Immunity against Liver Stage Plasmodium Infection
Murray, S. A., Mohar, I., Miller, J. L., Brempelis, K. J., Vaughan, A. M., Kappe, S. H. I., & Crispe, I. N. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1401724 · Cited by 20
“adopted widely for cells isolated from tissues where full recovery is impossible, such as the intestine (37).”
Intra- und extrazelluläre Signale während der T-Zellaktivierung und -differenzierung
Olbertz, J. H., Schmitt, E., & Radbruch, A. (2014) · doi:10.18452/17076
Caractérisation des lymphocytes T CD8+ spécifiques du VIH chez les « HIV controllers »
Hua, S. (2014) · doi:10.70675/ecedee2bza3a1z401az9ed7z2c1eaad3641b
“Il existe cependant une certaine hétérogénéité des cellules mémoires avec notamment la distinction entre deux sous populations de LT CD8 mémoires qui vont exprimer des marqueurs phénotypiques différents [156,157] : • les LT CD8 mémoires effecteurs (ME) qui sont CCR7 CD62L CD27 CD45RO et qui sont présents en périphérie,”
BackgroundGrund, L. Z. (2013) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2013.tde-07062014-124431
RELATIONSHIP BETWEEN CD8+ T CELL IMMUNITY AND AGING USING WEST NILE VIRUS INFECTION AS A MODEL
Lelic, A. (2013) · MacSphere (McMaster University) · doi:10.71548/21551
“The relative distribution of the memory T cell populations varies within tissues; a greater proportion of TCM can be found in the lymph nodes and tonsils whereas TEM are excluded from the lymph nodes and, instead, populate the periphery (spleen, skin, lung, liver and the gut) [174,175].”
Stather, D. (2012) · edoc Publication server (Humboldt University of Berlin) · doi:10.18452/16573
Strategies to Overcome Memory T Cells Mediatied Allograft Injury
Kim, B. S. (2012) · Korean Journal of Transplantation · doi:10.4285/jkstn.2012.26.2.69
“넷째, 기억 T 세포는 림프 조직뿐 아니라 비림프 조직에도 광범위하 게 존재한다(4,5).”
Nagler, C., & Wroblewska, J. (2011) · Nature Immunology · doi:10.1038/ni.2138
Gruta, N. L. L., & Turner, S. (2010) · Immunity · doi:10.1016/j.immuni.2010.07.007
“In contrast, studies have demonstrated that circulating memory CTL exhibit little or no expression of cytolytic machinery and display diminished in vivo and/or ex vivo cytolytic activity (Jenkins et al., 2007; Masopust et al., 2001).”
BackgroundResultInfluential
Metadata
- Authors
- Masopust, D., Vezys, V., Marzo, A. L., & Lefrançois, L.
- Affiliations
- UConn Health (US)
- Division of Immunology, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.
- Venue
- Science
- Published
- 2001-03-23
- Volume
- 291
- Issue
- 5512
- Pages
- 2413-2417
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2081097093
- Cited by
- 1,952
- References
- 0
- Citations by year
- 2026: 23 · 2025: 42 · 2024: 39 · 2023: 36 · 2022: 52 · 2021: 55 · 2020: 67 · 2019: 71 · 2018: 76 · 2017: 65 · 2016: 52 · 2015: 53 · 2014: 69 · 2013: 80 · 2012: 60
- FWCI
- 42.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI41576, T32 AI 07080, R01AI041576, T32AI007080)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK45260, R01DK045260)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- effector memory T cells, non-lymphoid tissues, CD8+ T cells, T cell migration, intracellular pathogens, viral infection, bacterial infection, lytic activity
- MeSH terms
- Animals, Cell Movement, Cells, Cultured, Flow Cytometry, H-2 Antigens, Immunologic Memory, Intestine, Small, Listeriosis, Listeria monocytogenes, Liver, Lung, Lymphocyte Activation, Lymphoid Tissue, Mice, Inbred C57BL, Ovalbumin, Phenotype, Vesicular stomatitis Indiana virus, T-Lymphocyte Subsets, Rhabdoviridae Infections, CD8-Positive T-Lymphocytes, Mice
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