Going Virtual as a Memory-Phenotype T Lymphocyte.

Animals; Humans; Mice; Phenotype; Lymphocyte Activation/immunology; Immunologic Memory; Memory T Cells/immunology; CD8-Positive T-Lymphocytes/immunology; Immunology and Allergy; Immunology

Abstract :

[en] Conventional or 'true' memory CD8+ T cells (TTM) arise from immunologically naive T cells that circulate in the periphery after selection in the thymus. During infection or immunization by a foreign antigen, naive T cells can receive antigen-specific activation signals after recognition of MHC-antigenic peptide complexes. But the CD8+ T-cell population in immunologically naive hosts is not restricted to circulating naive T cells expecting cognate antigen encounter. Indeed, memory-phenotype T cells (TMP) develop in the absence of foreign antigen encounter and therefore exist in naive, pathogen-free, as well as germ-free conditions. TMP have been shown to mediate bystander cell killing through innate mechanisms, as well as rapidly respond to cognate antigen stimulation. While the existence of foreign antigen-inexperienced TMP is now well acknowledged in laboratory mice, and also recognized in humans, the extensive nomenclature used for their description challenges the overall understanding of their multiple functions in health and disease. This article discusses the current understanding and controversies on the origin, maintenance and functions of the various populations recognized as TMP and highlights some potential challenges for deciphering their fate.

Disciplines :

Immunology & infectious disease

Author, co-author :

Yang, Bin ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire ; Department of Laboratory Medicine, Department of Developmental Immunology, Division of Molecular Hematology, Faculty of Medicine, Lund University, Lund, Sweden

Dewals, Benjamin G ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) > Immunologie vétérinaire ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium

Language :

English

Title :

Going Virtual as a Memory-Phenotype T Lymphocyte.

Publication date :

March 2026

Journal title :

European Journal of Immunology

ISSN :

0014-2980

eISSN :

1521-4141

Publisher :

John Wiley and Sons Inc, Germany

Volume :

Issue :

Pages :

e70174

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.70174

Available on ORBi :

since 28 March 2026

Statistics

Number of views

63 (3 by ULiège)

Number of downloads

32 (3 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

S. M. Kaech and W. Cui, “Transcriptional Control of Effector and Memory CD8+ T Cell Differentiation,” Nature Reviews Immunology 12 (2012): 749–761, https://doi.org/10.1038/nri3307.
T. Gebhardt, L. M. Wakim, L. Eidsmo, P. C. Reading, W. R. Heath, and F. R. Carbone, “Memory T Cells in Nonlymphoid Tissue That Provide Enhanced Local Immunity During Infection With herpes Simplex Virus,” Nature Immunology 10 (2009): 524–530, https://doi.org/10.1038/ni.1718.
S. Halle, O. Halle, and R. Förster, “Mechanisms and Dynamics of T Cell-Mediated Cytotoxicity in Vivo,” Trends in Immunology 38 (2017): 432–443, https://doi.org/10.1016/j.it.2017.04.002.
S. C. Jameson, “The Naming of Memory T-Cell Subsets,” Cold Spring Harbor Perspectives in Biology 13 (2021): 037788, https://doi.org/10.1101/cshperspect.a037788.
S. C. Jameson and D. Masopust, “Understanding Subset Diversity in T Cell Memory,” Immunity 48 (2018): 214–226, https://doi.org/10.1016/j.immuni.2018.02.010.
D. Masopust, V. Vezys, A. L. Marzo, and L. Lefrançois, “Preferential Localization of Effector Memory Cells in Nonlymphoid Tissue,” Science 291 (2001): 2413–2417, https://doi.org/10.1126/science.1058867.
D. Masopust, D. Choo, V. Vezys, et al., “Dynamic T Cell Migration Program Provides Resident Memory Within Intestinal Epithelium,” Journal of Experimental Medicine 207 (2010): 553–564, https://doi.org/10.1084/jem.20090858.
S. N. Mueller, T. Gebhardt, and F. R. Carbone, “Heath WR. Memory T Cell Subsets, Migration Patterns, and Tissue Residence,” Annual Review of Immunology 31 (2013): 137–161, https://doi.org/10.1146/annurev-immunol-032712-095954.
Y. Muroyama and E. J. Wherry, “Memory T-Cell Heterogeneity and Terminology,” Cold Spring Harbor Perspectives in Biology 13 (2021): a037929, https://doi.org/10.1101/cshperspect.a037929.
R. L. Reinhardt, A. Khoruts, R. Merica, T. Zell, and M. K. Jenkins, “Visualizing the Generation of Memory CD4 T Cells in the Whole Body,” Nature 410 (2001): 101–105, https://doi.org/10.1038/35065111.
F. Sallusto, D. Lenig, R. Förster, M. Lipp, and A. Lanzavecchia, “Two Subsets of Memory T Lymphocytes With Distinct Homing Potentials and Effector Functions,” Nature 401 (1999): 708–712, https://doi.org/10.1038/44385.
E. J. Wherry, V. Teichgräber, T. C. Becker, et al., “Lineage Relationship and Protective Immunity of Memory CD8 T Cell Subsets,” Nature Immunology 4 (2003): 225–234, https://doi.org/10.1038/ni889.
S. C. Jameson, Y. J. Lee, and K. A. Hogquist, “Innate Memory T Cells,” Advances in Immunology 126 (2015): 173–213, https://doi.org/10.1016/bs.ai.2014.12.001.
D. Thiele, N. L. Gruta, A. Nguyen, and T. Hussain, “Hiding in Plain Sight: Virtually Unrecognizable Memory Phenotype CD8+ T Cells,” International Journal of Molecular Sciences 21 (2020): 8626, https://doi.org/10.3390/ijms21228626.
J. T. White, E. W. Cross, and R. M. Kedl, “Antigen-inexperienced Memory CD8+ T Cells: Where They Come From and Why We Need Them,” Nature Reviews Immunology 17 (2017): 391–400, https://doi.org/10.1038/nri.2017.34.
C. Haluszczak, A. D. Akue, S. E. Hamilton, et al., “The Antigen-specific CD8+ T Cell Repertoire in Unimmunized Mice Includes Memory Phenotype Cells Bearing Markers of Homeostatic Expansion,” Journal of Experimental Medicine 206 (2009): 435–448, https://doi.org/10.1084/jem.20081829.
J. Sprent and C. D. Surh, “Normal T Cell Homeostasis: The Conversion of Naive Cells Into Memory-phenotype Cells,” Nature Immunology 12 (2011): 478–484, https://doi.org/10.1038/ni.2018.
H. Sun, C. Sun, W. Xiao, and R. Sun, “Tissue-resident Lymphocytes: From Adaptive to Innate Immunity,” Cellular & Molecular Immunology 16 (2019): 205–215, https://doi.org/10.1038/s41423-018-0192-y.
C. Tanchot, F. A. Lemonnier, B. Pérarnau, A. A. Freitas, and B. Rocha, “Differential Requirements for Survival and Proliferation of CD8 Naïve or Memory T Cells,” Science 276 (1997): 2057–2062, https://doi.org/10.1126/science.276.5321.2057.
S. R. M. Clarke and A. Y. Rudensky, “Survival and Homeostatic Proliferation of Naive Peripheral CD4+ T Cells in the Absence of Self Peptide:MHC Complexes,” The Journal of Immunology 165 (2000): 2458–2464, https://doi.org/10.4049/jimmunol.165.5.2458.
B. Ernst, D.-S. Lee, J. M. Chang, J. Sprent, and C. D. Surh, “The Peptide Ligands Mediating Positive Selection in the Thymus Control T Cell Survival and Homeostatic Proliferation in the Periphery,” Immunity 11 (1999): 173–181, https://doi.org/10.1016/S1074-7613(00)80092-8.
A. W. Goldrath and M. J. Bevan, “Low-Affinity Ligands for the TCR Drive Proliferation of Mature CD8+ T Cells in Lymphopenic Hosts,” Immunity 11 (1999): 183–190, https://doi.org/10.1016/S1074-7613(00)80093-X.
W. C. Kieper and S. C. Jameson, “Homeostatic Expansion and Phenotypic Conversion of Naïve T Cells in Response to Self Peptide/MHC Ligands,” Proceedings of the National Academy of Sciences 96 (1999): 13306–13311, https://doi.org/10.1073/pnas.96.23.13306.
K. Murali-Krishna and R. Ahmed, “Cutting Edge: Naive T Cells Masquerading as Memory Cells,” The Journal of Immunology 165 (2000): 1733–1737, https://doi.org/10.4049/jimmunol.165.4.1733.
S. C. Jameson, “Maintaining the Norm: T-cell Homeostasis,” Nature Reviews Immunology 2 (2002): 547–556, https://doi.org/10.1038/nri853.
S. E. Hamilton, M. C. Wolkers, S. P. Schoenberger, and S. C. Jameson, “The Generation of Protective Memory-Like CD8+ T Cells During Homeostatic Proliferation Requires CD4+ T Cells,” Nature Immunology 7 (2006): 475–481, https://doi.org/10.1038/ni1326.
C. D. Surh and J. Sprent, “Homeostasis of Naive and Memory T Cells,” Immunity 29 (2008): 848–862, https://doi.org/10.1016/j.immuni.2008.11.002.
E. B. Bell, S. M. Sparshott, M. T. Drayson, and W. L. Ford, “The Stable and Permanent Expansion of Functional T Lymphocytes in Athymic Nude Rats After a Single Injection of Mature T Cells,” Journal of immunology (Baltimore, Md: 1950) 139 (1987): 1379–1384.
B. Rocha, N. Dautigny, and P. Pereira, “Peripheral T Lymphocytes: Expansion Potential and Homeostatic Regulation of Pool Sizes and CD4/CD8 Ratios in Vivo,” European Journal of Immunology 19 (1989): 905–911, https://doi.org/10.1002/eji.1830190518.
M. Heidarian, S. K. Kannan, W. Swanson, T. S. Griffith, J. T. Harty, and V. P. Badovinac, “Delineating the Short- and Long-term Impact of Ionizing Radiation on Antigen-inexperienced CD8+ T Cell Subsets,” JCI Insight 10 (2025), Available at, https://doi.org/10.1172/jci.insight.194201.
C. D. Surh, O. Boyman, J. F. Purton, and J. Sprent, “Homeostasis of Memory T Cells,” Immunological Reviews 211 (2006): 154–163, https://doi.org/10.1111/j.0105-2896.2006.00401.x.
N. L. L. Gruta, W. T. Rothwell, T. Cukalac, et al., “Primary CTL Response Magnitude in Mice Is Determined by the Extent of Naive T Cell Recruitment and Subsequent Clonal Expansion,” Journal of Clinical Investigation 120 (2010): 1885–1894, https://doi.org/10.1172/JCI41538.
K. Takada and S. C. Jameson, “Naive T Cell Homeostasis: From Awareness of Space to a Sense of Place,” Nature Reviews Immunology 9 (2009): 823–832, https://doi.org/10.1038/nri2657.
J. Sprent, J.-H. Cho, O. Boyman, and C. D. Surh, “T Cell Homeostasis,” Immunology & Cell Biology 86 (2008): 312–319, https://doi.org/10.1038/icb.2008.12.
M. A. Weinreich, K. Takada, C. Skon, S. L. Reiner, S. C. Jameson, and K. A. Hogquist, “KLF2 Transcription-Factor Deficiency in T Cells Results in Unrestrained Cytokine Production and Upregulation of Bystander Chemokine Receptors,” Immunity 31 (2009): 122–130, https://doi.org/10.1016/j.immuni.2009.05.011.
M. A. Weinreich, O. A. Odumade, S. C. Jameson, and K. A. Hogquist, “T Cells Expressing the Transcription Factor PLZF Regulate the Development of Memory-Like CD8+ T Cells,” Nature Immunology 11 (2010): 709–716, https://doi.org/10.1038/ni.1898.
L. J. Berg, “Signalling Through TEC Kinases Regulates Conventional Versus Innate CD8+ T-cell Development,” Nature Reviews Immunology 7 (2007): 479–485, https://doi.org/10.1038/nri2091.
K. B. Urdahl, J. C. Sun, and M. J. Bevan, “Positive Selection of MHC Class Ib–restricted CD8+ T Cells on Hematopoietic Cells,” Nature Immunology 3 (2002): 772–779, https://doi.org/10.1038/ni814.
R. J. Salmond, R. J. Brownlie, V. L. Morrison, and R. Zamoyska, “The Tyrosine Phosphatase PTPN22 Discriminates Weak Self Peptides From Strong Agonist TCR Signals,” Nature Immunology 15 (2014): 875–883, https://doi.org/10.1038/ni.2958.
R. W. Dutton, L. M. Bradley, and S. L. Swain, “T Cell Memory,” Annual Review of Immunology 16 (1998): 201–223, https://doi.org/10.1146/annurev.immunol.16.1.201.
A. Bendelac, N. Killeen, D. R. Littman, and R. H. Schwartz, “A Subset of CD4 + Thymocytes Selected by MHC Class I Molecules,” Science 263 (1994): 1774–1778, https://doi.org/10.1126/science.7907820.
Z. Kurepa, J. Su, and J. Forman, “Memory Phenotype of CD8+ T Cells in MHC Class Ia-Deficient Mice,” The Journal of Immunology 170 (2003): 5414–5420, https://doi.org/10.4049/jimmunol.170.11.5414.
I. Kawachi, J. Maldonado, C. Strader, and S. Gilfillan, “MR1-Restricted Vα19 i Mucosal-Associated Invariant T Cells Are Innate T Cells in the Gut Lamina Propria That Provide a Rapid and Diverse Cytokine Response,” The Journal of Immunology 176 (2006): 1618–1627, https://doi.org/10.4049/jimmunol.176.3.1618.
A. H. Andreotti, P. L. Schwartzberg, R. E. Joseph, and L. J. Berg, “T-Cell Signaling Regulated by the Tec Family Kinase, Itk,” Cold Spring Harbor Perspectives in Biology 2 (2010): a002287–a002287, https://doi.org/10.1101/cshperspect.a002287.
Y. J. Lee, K. L. Holzapfel, J. Zhu, S. C. Jameson, and K. A. Hogquist, “Steady-state Production of IL-4 Modulates Immunity in Mouse Strains and Is Determined by Lineage Diversity of iNKT Cells,” Nature Immunology 14 (2013): 1146–1154, https://doi.org/10.1038/ni.2731.
Y. J. Lee, S. C. Jameson, and K. A. Hogquist, “Alternative Memory in the CD8 T Cell Lineage,” Trends in Immunology 32 (2011): 50–56, https://doi.org/10.1016/j.it.2010.12.004.
W. Huang, F. Huang, A. K. Kannan, J. Hu, and A. August, “ITK Tunes IL-4-induced Development of Innate Memory CD8+ T Cells in a Γδ T and Invariant NKT Cell-Independent Manner,” Journal of Leukocyte Biology 96 (2014): 55–63, https://doi.org/10.1189/jlb.1AB0913-484RR.
M. E. Viano, N. S. Baez, C. Savid-Frontera, et al., “Virtual Memory CD8 + T Cells: Origin and beyond,” Journal of Interferon & Cytokine Research 42 (2022): 624–642, https://doi.org/10.1089/jir.2022.0053.
D. Lai, J. Zhu, T. Wang, et al., “KLF13 sustains Thymic Memory-Like CD8+ T Cells in BALB/c Mice by Regulating IL-4–Generating Invariant Natural Killer T Cells,” Journal of Experimental Medicine 208 (2011): 1093–1103, https://doi.org/10.1084/jem.20101527.
C. H. Miller, D. E. J. Klawon, S. Zeng, V. Lee, N. D. Socci, and P. A. Savage, “Eomes Identifies Thymic Precursors of Self-Specific Memory-Phenotype CD8+ T Cells,” Nature Immunology 21 (2020): 567–577, https://doi.org/10.1038/s41590-020-0653-1.
S. Hou, T. Shao, T. Mao, et al., “Virtual Memory T Cells Orchestrate Extralymphoid Responses Conducive to Resident Memory,” Science Immunology 6 (2021), https://doi.org/10.1126/sciimmunol.abg9433.
T. Sosinowski, J. T. White, E. W. Cross, et al., “CD8α+ Dendritic Cell Trans Presentation of IL-15 to Naive CD8+ T Cells Produces Antigen-Inexperienced T Cells in the Periphery With Memory Phenotype and Function,” The Journal of Immunology 190 (2013): 1936–1947, https://doi.org/10.4049/jimmunol.1203149.
J. Nikolich-Žugich, “Ageing and Life-long Maintenance of T-Cell Subsets in the Face of Latent Persistent Infections,” Nature Reviews Immunology 8 (2008): 512–522, https://doi.org/10.1038/nri2318.
B. D. Rudd, V. Venturi, G. Li, et al., “Nonrandom Attrition of the Naive CD8 + T-Cell Pool With Aging Governed by T-cell Receptor: PMHC Interactions,” Proceedings of the National Academy of Sciences 108 (2011): 13694–13699, https://doi.org/10.1073/pnas.1107594108.
T. Hussain and K. M. Quinn, “Similar but Different: Virtual Memory CD8 T Cells as a Memory-Like Cell Population,” Immunology & Cell Biology 97 (2019): 675–684, https://doi.org/10.1111/imcb.12277.
N. L. Smith, R. K. Patel, A. Reynaldi, et al., “Developmental Origin Governs CD8+ T Cell Fate Decisions During Infection,” Cell 174 (2018): 117–130.e14, https://doi.org/10.1016/j.cell.2018.05.029.
M. P. Davenport, N. L. Smith, and B. D. Rudd, “Building a T Cell Compartment: How Immune Cell Development Shapes Function,” Nature Reviews Immunology 20 (2020): 499–506, https://doi.org/10.1038/s41577-020-0332-3.
A. D. Akue, J.-Y. Lee, and S. C. Jameson, “Derivation and Maintenance of Virtual Memory CD8 T Cells,” The Journal of Immunology 188 (2012): 2516–2523, https://doi.org/10.4049/jimmunol.1102213.
N. B. Watson, R. K. Patel, C. Kean, et al., “The Gene Regulatory Basis of Bystander Activation in CD8 + T Cells,” Science Immunology 9 (2024), https://doi.org/10.1126/sciimmunol.adf8776.
B.-C. Chiu, B. E. Martin, V. R. Stolberg, and S. W. Chensue, “Cutting Edge: Central Memory CD8 T Cells in Aged Mice Are Virtual Memory Cells,” The Journal of Immunology 191 (2013): 5793–5796, https://doi.org/10.4049/jimmunol.1302509.
K. M. Quinn, A. Fox, K. L. Harland, et al., “Age-Related Decline in Primary CD8+ T Cell Responses Is Associated With the Development of Senescence in Virtual Memory CD8+ T Cells,” Cell Reports 23 (2018): 3512–3524, https://doi.org/10.1016/j.celrep.2018.05.057.
K. M. Quinn, T. Hussain, F. Kraus, et al., “Metabolic Characteristics of CD8+ T Cell Subsets in Young and Aged Individuals Are Not Predictive of Functionality,” Nature Communications 11 (2020): 2857, https://doi.org/10.1038/s41467-020-16633-7.
M. Borsa, N. Barandun, F. Gräbnitz, et al., “Asymmetric Cell Division Shapes Naive and Virtual Memory T-cell Immunity During Ageing,” Nature Communications 12 (2021): 2715, https://doi.org/10.1038/s41467-021-22954-y.
K. G. Lanzer, T. Cookenham, W. W. Reiley, and M. A. Blackman, “Virtual Memory Cells Make a Major Contribution to the Response of Aged Influenza-Naïve Mice to Influenza Virus Infection,” Immunity & Ageing 15 (2018): 17, https://doi.org/10.1186/s12979-018-0122-y.
A. Moudra, V. Niederlova, J. Novotny, et al., “Phenotypic and Clonal Stability of Antigen-Inexperienced Memory-Like T Cells Across the Genetic Background, Hygienic Status, and Aging,” The Journal of Immunology 206 (2021): 2109–2121, https://doi.org/10.4049/jimmunol.2001028.
M. Prlic, L. Lefrancois, and S. C. Jameson, “Multiple Choices,” The Journal of Experimental Medicine 195 (2002): F49–F52, https://doi.org/10.1084/jem.20020767.
A. W. Goldrath, L. Y. Bogatzki, and M. J. Bevan, “Naive T Cells Transiently Acquire a Memory-Like Phenotype During Homeostasis-Driven Proliferation,” The Journal of Experimental Medicine 192 (2000): 557–564, https://doi.org/10.1084/jem.192.4.557.
Q. Ge, H. Hu, H. N. Eisen, and J. Chen, “Different Contributions of Thymopoiesis and Homeostasis-Driven Proliferation to the Reconstitution of Naive and Memory T Cell Compartments,” Proceedings of the National Academy of Sciences 99 (2002): 2989–2994, https://doi.org/10.1073/pnas.052714099.
C. Tanchot, A. L. Campion, B. Martin, S. Léaument, N. Dautigny, and B. Lucas, “Conversion of Naive T Cells to a Memory-Like Phenotype in Lymphopenic Hosts Is Not Related to a Homeostatic Mechanism That Fills the Peripheral Naive T Cell Pool,” The Journal of Immunology 168 (2002): 5042–5046, https://doi.org/10.4049/jimmunol.168.10.5042.
K. S. Schluns, W. C. Kieper, S. C. Jameson, and L. Lefrançois, “Interleukin-7 Mediates the Homeostasis of Naïve and Memory CD8 T Cells in Vivo,” Nature Immunology 1 (2000): 426–432, https://doi.org/10.1038/80868.
M. M. Sandau, C. J. Winstead, and S. C. Jameson, “IL-15 Is Required for Sustained Lymphopenia-Driven Proliferation and Accumulation of CD8 T Cells,” The Journal of Immunology 179 (2007): 120–125, https://doi.org/10.4049/jimmunol.179.1.120.
A. Xu, K. K. Bhanumathy, J. Wu, et al., “IL-15 Signaling Promotes Adoptive Effector T-Cell Survival and Memory Formation in Irradiation-Induced Lymphopenia,” Cell & Bioscience 6 (2016): 30, https://doi.org/10.1186/s13578-016-0098-2.
A. W. Goldrath, P. V. Sivakumar, M. Glaccum, et al., “Cytokine Requirements for Acute and Basal Homeostatic Proliferation of Naive and Memory CD8+ T Cells,” The Journal of Experimental Medicine 195 (2002): 1515–1522, https://doi.org/10.1084/jem.20020033.
J. T. Tan, B. Ernst, W. C. Kieper, E. LeRoy, J. Sprent, and C. D. Surh, “Interleukin (IL)-15 and IL-7 Jointly Regulate Homeostatic Proliferation of Memory Phenotype CD8+ Cells but Are Not Required for Memory Phenotype CD4+ Cells,” The Journal of Experimental Medicine 195 (2002): 1523–1532, https://doi.org/10.1084/jem.20020066.
K. S. Schluns, K. Williams, A. Ma, X. X. Zheng, and L. Lefrançois, “Cutting Edge: Requirement for IL-15 in the Generation of Primary and Memory Antigen-Specific CD8 T Cells,” The Journal of Immunology 168 (2002): 4827–4831, https://doi.org/10.4049/jimmunol.168.10.4827.
T. C. Becker, E. J. Wherry, D. Boone, et al., “Interleukin 15 Is Required for Proliferative Renewal of Virus-Specific Memory CD8 T Cells,” The Journal of Experimental Medicine 195 (2002): 1541–1548, https://doi.org/10.1084/jem.20020369.
J.-H. Cho, O. Boyman, H.-O. Kim, et al., “An Intense Form of Homeostatic Proliferation of Naive CD8+ Cells Driven by IL-2,” The Journal of Experimental Medicine 204 (2007): 1787–1801, https://doi.org/10.1084/jem.20070740.
C. Ramsey, M. P. Rubinstein, D. M. Kim, J.-H. Cho, J. Sprent, and C. D. Surh, “The Lymphopenic Environment of CD132 (Common γ-Chain)-Deficient Hosts Elicits Rapid Homeostatic Proliferation of Naive T Cells via IL-15,” The Journal of Immunology 180 (2008): 5320–5326, https://doi.org/10.4049/jimmunol.180.8.5320.
G. M. Davey, R. Starr, A. L. Cornish, et al., “SOCS-1 Regulates IL-15–Driven Homeostatic Proliferation of Antigen-Naive CD8 T Cells, Limiting Their Autoimmune Potential,” The Journal of Experimental Medicine 202 (2005): 1099–1108, https://doi.org/10.1084/jem.20050003.
S. Ramanathan, J. Gagnon, C. Leblanc, R. Rottapel, and S. Ilangumaran, “Suppressor of Cytokine Signaling 1 Stringently Regulates Distinct Functions of IL-7 and IL-15 in Vivo During T Lymphocyte Development and Homeostasis,” The Journal of Immunology 176 (2006): 4029–4041, https://doi.org/10.4049/jimmunol.176.7.4029.
J. T. White, E. W. Cross, M. A. Burchill, et al., “Virtual Memory T Cells Develop and Mediate Bystander Protective Immunity in an IL-15-dependent Manner,” Nature Communications 7 (2016): 11291, https://doi.org/10.1038/ncomms11291.
D. F. Tough, X. Zhang, and J. Sprent, “An IFN-γ-Dependent Pathway Controls Stimulation of Memory Phenotype CD8+ T Cell Turnover in Vivo by IL-12, IL-18, and IFN-γ,” The Journal of Immunology 166 (2001): 6007–6011, https://doi.org/10.4049/jimmunol.166.10.6007.
Ö. Sercan, D. Stoycheva, G. J. Hämmerling, B. Arnold, and T. Schüler, “IFN-γ Receptor Signaling Regulates Memory CD8+ T Cell Differentiation,” The Journal of Immunology 184 (2010): 2855–2862, https://doi.org/10.4049/jimmunol.0902708.
H. J. Park, S. M. Choi, E. A. Choi, H. J. Boo, J. I. Lee, and K. C. Jung, “IL-4, IL-15, and Type I Interferon Orchestrate the Shaping of the Heterogeneity of Virtual Memory CD8 T Cells,” European Journal of Immunology 55 (2025), Available at:, https://doi.org/10.1002/eji.202451765.
X. Zhang, S. Sun, I. Hwang, D. F. Tough, and J. Sprent, “Potent and Selective Stimulation of Memory-Phenotype CD8+ T Cells in Vivo by IL-15,” Immunity 8 (1998): 591–599, https://doi.org/10.1016/S1074-7613(00)80564-6.
X. Zhang, H. Fujii, H. Kishimoto, E. LeRoy, C. D. Surh, and J. Sprent, “Aging Leads to Disturbed Homeostasis of Memory Phenotype CD8+ Cells,” The Journal of Experimental Medicine 195 (2002): 283–293, https://doi.org/10.1084/jem.20011267.
V. Martinet, S. Tonon, D. Torres, et al., “Type I Interferons Regulate Eomesodermin Expression and the Development of Unconventional Memory CD8+ T Cells,” Nature Communications 6 (2015): 7089, https://doi.org/10.1038/ncomms8089.
L. F. K. Uhl, H. Cai, S. L. Oram, et al., “Interferon-γ Couples CD8+ T Cell Avidity and Differentiation During Infection,” Nature Communications 14 (2023): 6727, https://doi.org/10.1038/s41467-023-42455-4.
K. R. Renkema, J.-Y. Lee, Y. J. Lee, S. E. Hamilton, K. A. Hogquist, and S. C. Jameson, “IL-4 Sensitivity Shapes the Peripheral CD8+ T Cell Pool and Response to Infection,” Journal of Experimental Medicine 213 (2016): 1319–1329, https://doi.org/10.1084/jem.20151359.
H.-J. Park, A. Lee, J.-I. Lee, S. H. Park, S.-J. Ha, and K. C. Jung, “Effect of IL-4 on the Development and Function of Memory-Like CD8 T Cells in the Peripheral Lymphoid Tissues,” Immune Network 16 (2016): 126, https://doi.org/10.4110/in.2016.16.2.126.
M. Rolot, A. M. Dougall, A. Chetty, et al., “Helminth-Induced IL-4 Expands Bystander Memory CD8+ T Cells for Early Control of Viral Infection,” Nature Communications 9 (2018): 4516, https://doi.org/10.1038/s41467-018-06978-5.
B. Yang, O. Piedfort, G. Sanchez-Sanchez, et al., “IL-4 Induces CD22 Expression to Restrain the Effector Program of Virtual Memory T Cells,” Science Immunology 10 (2025), https://doi.org/10.1126/sciimmunol.adk4841.
P. Tripathi, S. C. Morris, C. Perkins, A. Sholl, F. D. Finkelman, and D. A. Hildeman, “IL-4 and IL-15 Promotion of Virtual Memory CD8+ T Cells Is Determined by Genetic Background,” European Journal of Immunology 46 (2016): 2333–2339, https://doi.org/10.1002/eji.201646404.
S. A. Carty, G. A. Koretzky, and M. S. Jordan, “Interleukin-4 Regulates Eomesodermin in CD8+ T Cell Development and Differentiation Freitas AA, Ed,” PLoS ONE 9 (2014): e106659, https://doi.org/10.1371/journal.pone.0106659.
I. Kavazović, H. Han, G. Balzaretti, et al., “Eomes Broadens the Scope of CD8 T-cell Memory by Inhibiting Apoptosis in Cells of Low Affinity Marrack P,” PLoS Biology 18 (2020): e3000648, https://doi.org/10.1371/journal.pbio.3000648.
S. M. Choi, H. J. Park, H. J. Boo, K. C. Jung, and J. I. Lee, “Characterization of CD8+ Virtual Memory T Cells in IL-4 Knockout Mice Using Single-Cell RNA Sequencing,” Biochemical and Biophysical Research Communications 738 (2024): 150950, https://doi.org/10.1016/j.bbrc.2024.150950.
P. Tripathi, S. C. Morris, C. Perkins, A. Sholl, F. D. Finkelman, and D. A. Hildeman, “IL-4 and IL-15 Promotion of Virtual Memory CD8 + T Cells Is Determined by Genetic Background,” European Journal of Immunology 46 (2016): 2333–2339, https://doi.org/10.1002/eji.201646404.
N. Istaces, M. Splittgerber, V. L. Silva, et al., “EOMES Interacts With RUNX3 and BRG1 to Promote Innate Memory Cell Formation Through Epigenetic Reprogramming,” Nature Communications 10 (2019): 3306, https://doi.org/10.1038/s41467-019-11233-6.
E. M. Kwesi-Maliepaard, M. A. Aslam, M. F. Alemdehy, et al., “The Histone Methyltransferase DOT1L Prevents Antigen-Independent Differentiation and Safeguards Epigenetic Identity of CD8 + T Cells,” Proceedings of the National Academy of Sciences 117 (2020): 20706–20716, https://doi.org/10.1073/pnas.1920372117.
B. Bhatt, K. Kumar, H. Shi, et al., “UFL1 Promotes Survival and Function of Virtual Memory CD8 T Cells,” The Journal of Immunology 214 (2025): 446–459, https://doi.org/10.1093/jimmun/vkae042.
S. Pokhrel, D. M. Jones, M. R. Leonard, et al., “Aiolos Restricts the Generation of Antigen-Inexperienced, Virtual Memory CD8 + T Cells,” (2025), https://doi.org/10.1101/2025.06.11.659122.
J. N. Mandl, J. P. Monteiro, N. Vrisekoop, and R. N. Germain, “T Cell-Positive Selection Uses Self-Ligand Binding Strength to Optimize Repertoire Recognition of Foreign Antigens,” Immunity 38 (2013): 263–274, https://doi.org/10.1016/j.immuni.2012.09.011.
A. Tarakhovsky, S. B. Kanner, J. Hombach, et al., “A Role for CD5 in TCR-Mediated Signal Transduction and Thymocyte Selection,” Science 269 (1995): 535–537, https://doi.org/10.1126/science.7542801.
W. C. Kieper, J. T. Burghardt, and C. D. Surh, “A Role for TCR Affinity in Regulating Naive T Cell Homeostasis,” Journal of Immunology 172 (2004): 40–44, https://doi.org/10.4049/jimmunol.172.1.40.
R. B. Fulton, S. E. Hamilton, Y. Xing, et al., “The TCR's Sensitivity to Self Peptide–MHC Dictates the Ability of Naive CD8+ T Cells to Respond to Foreign Antigens,” Nature Immunology 16 (2015): 107–117, https://doi.org/10.1038/ni.3043.
L. K. Swee, Z. W. Tan, A. Sanecka, et al., “Peripheral Self-reactivity Regulates Antigen-Specific CD8 T-Cell Responses and Cell Division Under Physiological Conditions,” Open Biol 6 (2016): 160293, https://doi.org/10.1098/rsob.160293.
A. Drobek, A. Moudra, D. Mueller, et al., “Strong Homeostatic TCR Signals Induce Formation of Self-Tolerant Virtual Memory CD8 T Cells,” The EMBO Journal 37 (2018), https://www.embopress.org/doi/10.15252/embj.201798518.
D. Paprckova, V. Niederlova, A. Moudra, et al., “Self-reactivity of CD8 T-Cell Clones Determines Their Differentiation Status Rather Than Their Responsiveness in Infections,” Frontiers in Immunology 13 (2022), https://doi.org/10.3389/fimmu.2022.1009198.
M. Prasad, L. Wojciech, J. Brzostek, et al., “Expansion of an Unusual Virtual Memory CD8+ Subpopulation Bearing Vα3.2 TCR in Themis-Deficient Mice,” Frontiers in Immunology 12 (2021), https://doi.org/10.3389/fimmu.2021.644483.
V. S. Mahajan, E. Demissie, F. Alsufyani, et al., “DOCK2 Sets the Threshold for Entry Into the Virtual Memory CD8+ T Cell Compartment by Negatively Regulating Tonic TCR Triggering,” The Journal of Immunology 204 (2020): 49–57, https://doi.org/10.4049/jimmunol.1900440.
M. E. Badr, Z. Zhang, X. Tai, and A. Singer, “CD8 T Cell Tolerance Results From Eviction of Immature Autoreactive Cells From the thymus,” Science 382 (2023): 534–541, https://doi.org/10.1126/science.adh4124.
D. M. Richards, B. Kyewski, and M. Feuerer, “Re-examining the Nature and Function of Self-Reactive T Cells,” Trends in Immunology 37 (2016): 114–125, https://doi.org/10.1016/j.it.2015.12.005.
J.-Y. Lee, S. E. Hamilton, A. D. Akue, K. A. Hogquist, and S. C. Jameson, “Virtual Memory CD8 T Cells Display Unique Functional Properties,” Proceedings of the National Academy of Sciences 110 (2013): 13498–13503, https://doi.org/10.1073/pnas.1307572110.
N. S. Baez, F. Cerbán, C. Savid-Frontera, et al., “Thymic Expression of IL-4 and IL-15 After Systemic Inflammatory or Infectious Th1 Disease Processes Induce the Acquisition of ‘Innate’ characteristics During CD8+ T Cell Development Sacks D,” PLOS Pathogens 15 (2019): e1007456, https://doi.org/10.1371/journal.ppat.1007456.
N. J. Maurice, M. J. McElrath, E. Andersen-Nissen, N. Frahm, and M. Prlic, “CXCR3 enables Recruitment and Site-Specific Bystander Activation of Memory CD8+ T Cells,” Nature Communications 10 (2019): 4987, https://doi.org/10.1038/s41467-019-12980-2.
J. S. Lin, K. Mohrs, F. M. Szaba, L. W. Kummer, E. A. Leadbetter, and M. Mohrs, “Virtual Memory CD8 T Cells Expanded by Helminth Infection Confer Broad Protection Against Bacterial Infection,” Mucosal Immunology 12 (2019): 258–264, https://doi.org/10.1038/s41385-018-0100-x.
X. Wang, B. C. Waschke, R. A. Woolaver, S. M. Y. Chen, Z. Chen, and J. H. Wang, “MHC Class I-Independent Activation of Virtual Memory CD8 T Cells Induced by Chemotherapeutic Agent-Treated Cancer Cells,” Cellular & Molecular Immunology 18 (2021): 723–734, https://doi.org/10.1038/s41423-020-0463-2.
C. Savid-Frontera, M. E. Viano, N. S. Baez, et al., “Exploring the Immunomodulatory Role of Virtual Memory CD8+ T Cells: Role of IFN Gamma in Tumor Growth Control,” Frontiers in Immunology 13 (2022), https://doi.org/10.3389/fimmu.2022.971001.
A. S. D. Costa, J. B. Graham, J. L. Swarts, and J. M. Lund, “Regulatory T Cells Limit Unconventional Memory to Preserve the Capacity to Mount Protective CD8 Memory Responses to Pathogens,” Proceedings of the National Academy of Sciences 116 (2019): 9969–9978, https://doi.org/10.1073/pnas.1818327116.
J. Seok, S.-D. Cho, J. Lee, et al., “A Virtual Memory CD8+ T Cell-Originated Subset Causes Alopecia Areata Through Innate-Like Cytotoxicity,” Nature Immunology 24 (2023): 1308–1317, https://doi.org/10.1038/s41590-023-01547-5.
K. Akane, S. Kojima, T. W. Mak, H. Shiku, and H. Suzuki, “CD8 + CD122 + CD49d low Regulatory T Cells Maintain T-cell Homeostasis by Killing Activated T Cells via Fas/FasL-Mediated Cytotoxicity,” Proceedings of the National Academy of Sciences 113 (2016): 2460–2465, https://doi.org/10.1073/pnas.1525098113.
H.-J. Kim, X. Wang, S. Radfar, T. J. Sproule, D. C. Roopenian, and H. Cantor, “CD8 + T Regulatory Cells Express the Ly49 Class I MHC Receptor and Are Defective in Autoimmune Prone B6-Yaa Mice,” Proceedings of the National Academy of Sciences 108 (2011): 2010–2015, https://doi.org/10.1073/pnas.1018974108.
J. Li, M. Zaslavsky, Y. Su, et al., “KIR + CD8 + T Cells Suppress Pathogenic T Cells and Are Active in Autoimmune Diseases and COVID-19,” Science 376 (2022), https://doi.org/10.1126/science.abi9591.
H. S. Warren, P. M. Rana, D. T. Rieger, K. A. Hewitt, J. E. Dahlstrom, and A. L. Kent, “CD8 T Cells Expressing Killer Ig-Like Receptors and NKG2A Are Present in Cord Blood and Express a More Naïve Phenotype Than Their Counterparts in Adult Blood,” Journal of Leukocyte Biology 79 (2006): 1252–1259, https://doi.org/10.1189/jlb.0905536.
H. S. Min, Y. J. Lee, Y. K. Jeon, et al., “MHC Class II-Restricted Interaction Between Thymocytes Plays an Essential Role in the Production of Innate CD8+ T Cells,” The Journal of Immunology 186 (2011): 5749–5757, https://doi.org/10.4049/jimmunol.1002825.
S. He, C.-L. Luo, T. Luo, et al., “Systemic Immune Activity Occurs During Human Immune System Maturation,” Cell 188 (2025): 7291–7308.e23, https://doi.org/10.1016/j.cell.2025.10.003.
Y. J. Lee, Y. K. Jeon, B. H. Kang, et al., “Generation of PLZF+ CD4+ T Cells via MHC Class II–dependent Thymocyte–Thymocyte Interaction Is a Physiological Process in Humans,” Journal of Experimental Medicine 207 (2010): 237–246, https://doi.org/10.1084/jem.20091519.
D. Herndler-Brandstetter, S. Brunner, D. Weiskopf, et al., “Post-thymic Regulation of CD5 Levels in Human Memory T Cells Is Inversely Associated With the Strength of Responsiveness to Interleukin-15,” Human Immunology 72 (2011): 627–631, https://doi.org/10.1016/j.humimm.2011.03.028.
J. Geginat, A. Lanzavecchia, and F. Sallusto, “Proliferation and Differentiation Potential of human CD8+ Memory T-cell Subsets in Response to Antigen or Homeostatic Cytokines,” Blood 101 (2003): 4260–4266, https://doi.org/10.1182/blood-2002-11-3577.
A. M. Intlekofer, N. Takemoto, E. J. Wherry, et al., “Effector and Memory CD8+ T Cell Fate Coupled by T-bet and Eomesodermin,” Nature Immunology 6 (2005): 1236–1244, https://doi.org/10.1038/ni1268.
D. Kasakovski, X. Zeng, J. Lai, et al., “Characterization of KIR + NKG2A + Eomes− NK-Like CD8+ T Cells and Their Decline With Age in Healthy Individuals,” Cytometry Part B: Clinical Cytometry 100 (2021): 467–475, https://doi.org/10.1002/cyto.b.21945.
F. Jacomet, E. Cayssials, S. Basbous, et al., “Evidence for Eomesodermin-Expressing Innate-Like CD8 + KIR/NKG2A + T Cells in human Adults and Cord Blood Samples,” European Journal of Immunology 45 (2015): 1926–1933, https://doi.org/10.1002/eji.201545539.
D. K. J. Pieren, N. A. M. Smits, J. Hoeboer, et al., “Regulatory KIR + RA + T Cells Accumulate With Age and Are Highly Activated During Viral respiratory Disease,” Aging Cell 20 (2021), https://doi.org/10.1111/acel.13372.
A. B. Vasandan, H. A. Abdelsamed, S. K. Boi, et al., “Innate-Like Memory T Cells Rapidly Emerge in Humans After Gene Therapy for SCID-X1,” Immunity 58 (2025): 1922–1930.e3, https://doi.org/10.1016/j.immuni.2025.07.002.
R. Schreurs, M. E. Baumdick, A. F. Sagebiel, et al., “Human Fetal TNF-α-Cytokine-Producing CD4+ Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life,” Immunity 50 (2019): 462–476.e8, https://doi.org/10.1016/j.immuni.2018.12.010.
J. Kim, D.-Y. Chang, H. W. Lee, et al., “Innate-Like Cytotoxic Function of Bystander-Activated CD8+ T Cells Is Associated With Liver Injury in Acute Hepatitis A,” Immunity 48 (2018): 161–173.e5, https://doi.org/10.1016/j.immuni.2017.11.025.
T.-S. Kim and E.-C. Shin, “The Activation of Bystander CD8+ T Cells and Their Roles in Viral Infection,” Experimental & Molecular Medicine 51 (2019): 1–9, https://doi.org/10.1038/s12276-019-0316-1.
I.-H. Seo, H. S. Eun, J. K. Kim, et al., “IL-15 Enhances CCR5-mediated Migration of Memory CD8+ T Cells by Upregulating CCR5 Expression in the Absence of TCR Stimulation,” Cell Reports 36 (2021): 109438, https://doi.org/10.1016/j.celrep.2021.109438.
W. Hu, Y.-J. Li, C. Zhen, et al., “CCL5-Secreting Virtual Memory CD8+ T Cells Inversely Associate with Viral Reservoir Size in HIV-1−Infected Individuals on Antiretroviral Therapy,” Frontiers in Immunology 13 (2022), https://www.frontiersin.org/articles/10.3389/fimmu.2022.897569, Available at.
M. D. Martin and V. P. Badovinac, “Defining Memory CD8 T Cell,” Frontiers in Immunology 9 (2018), https://www.frontiersin.org/article/10.3389/fimmu.2018.02692, Available at.