Acquired transcriptional programming in functional and exhausted virus-specific CD8 T cells.
Open accessAbstract
PURPOSE OF REVIEW: Failure to control viral infections such as HIV results in T-cell receptor (TCR) and inhibitory receptor driven exhaustion of antigen-specific T cells. Persistent signaling by these receptors during chronic viral infection sculpts the transcriptional regulatory programs of virus-specific T cells. The resulting gene expression profile is tailored to temper the potentially damaging effector functions of cytotoxic T cells and adapt them to an antigen-rich and inflammation-rich environment. Here we review recent studies investigating mechanisms of transcriptional regulation of effector, functional memory, and exhausted T-cell functions during acute versus chronic infections. RECENT FINDINGS: Patterns of gene expression in virus-specific CD8 T cells are a result of a combination of pro and inhibitory signals from antigen presentation (TCR-mediated) and co-inhibitory receptor ligation (PD-1, 2B4). Further, memory-specific transcriptional regulation of 2B4 expression and signaling impose a self-limiting secondary effector response to a prolonged viral infection. Additionally, differentiation of functional memory CD8 T cells is coupled with acquisition of a repressive epigenetic program for PD-1 expression. However, chronic infection provides a signal that blocks the acquisition of these epigenetic modifications reinforcing the suppression of cytotoxic lymphocyte (CTL) functions in exhausted cells. SUMMARY: Current findings suggest that the mechanism(s) that delineate functional memory versus exhaustion are coupled with acquisition of transcriptional programs at the effector stage of differentiation, reinforced by cessation or persistence of TCR signaling.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Senescent T cells are phenotypically and functionally distinct from exhausted T cells induced by prolonged antigen stimulation.
“Based on phenotype and function, senescent T cells must not be confused with exhausted T cells induced by prolonged antigen stimulation [40–42].”
From T-cell aging in rheumatoid arthritis (2014) · cites this paper as [40]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Restoring function in exhausted CD8 T cells during chronic viral infection
Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2005) · Nature · doi:10.1038/nature04444 · Cited by 3,960 · see citing works
Self-citationPD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
Day, C. L., Kaufmann, D. E., Kiepiela, P., Brown, J. A., Moodley, E. S., Reddy, S., Mackey, E. W., Miller, J. D., Leslie, A. J., DePierres, C., et al. (2006) · Nature · doi:10.1038/nature05115 · Cited by 2,680 · see citing works
Self-citationMolecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103 · see citing works
Self-citationCounting Antigen-Specific CD8 T Cells: A Reevaluation of Bystander Activation during Viral Infection
Murali‐Krishna, K., Altman, J. D., Suresh, M., Sourdive, D. J. D., Zajac, A. J., Miller, J. D., Slansky, J. E., & Ahmed, R. (1998) · Immunity · doi:10.1016/s1074-7613(00)80470-7 · Cited by 1,918 · see citing works
Self-citationChromatin modification and epigenetic reprogramming in mammalian development
Li, E. (2002) · Nature Reviews Genetics · doi:10.1038/nrg887 · Cited by 1,900 · see citing works
Lineage relationship and protective immunity of memory CD8 T cell subsets
Wherry, E. J., Teichgräber, V., Becker, T. C., Masopust, D., Kaech, S. M., Antia, R., von Andrian, U. H., & Ahmed, R. (2003) · Nature Immunology · doi:10.1038/ni889 · Cited by 1,864 · see citing works
Self-citationKaech, S. M., Tan, J. T., Wherry, E. J., Konieczny, B. T., Surh, C. D., & Ahmed, R. (2003) · Nature Immunology · doi:10.1038/ni1009 · Cited by 1,830 · cited 2× · see citing works
“Unau 1746-630X 2011 Wolters Kluwer Health | Lippincott Williams & Wilki The cell-intrinsic mechanisms that dictate the functional, or lack thereof, capabilities of virusspecific CD8 T cells are initiated at the effector stage of differentiation, and are dependent upon strength and duration of TCR signaling [18,19].”
BackgroundSelf-citationHIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells
Betts, M. R. (2006) · Blood · doi:10.1182/blood-2005-12-4818 · Cited by 1,829 · see citing works
Immunological memory and protective immunity: understanding their relation
Ahmed, R., & Gray, D. (1996) · Science · doi:10.1126/science.272.5258.54 · Cited by 1,775 · see citing works
Self-citationMolecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.11.006 · Cited by 1,355 · see citing works
Self-citationA Critical Role for Dnmt1 and DNA Methylation in T Cell Development, Function, and Survival
Lee, P. P., Fitzpatrick, D. R., Beard, C., Jessup, H. K., Lehar, S. M., Makar, K. W., Pérez‐Melgosa, M., Sweetser, M. T., Schlissel, M. S., Nguyen, S. P., et al. (2001) · Immunity · doi:10.1016/s1074-7613(01)00227-8 · Cited by 1,280 · see citing works
Molecular and functional profiling of memory CD8 T cell differentiation.
Kaech, S., Hemby, S., Kersh, E., & Ahmed, R. (2002) · Cell · doi:10.1016/s0092-8674(02)01139-x · Cited by 1,081 · see citing works
Self-citationCao, Y., Qin, L., Zhang, L., Safrit, J. T., & Ho, D. D. (1995) · New England Journal of Medicine · doi:10.1056/nejm199501263320401 · Cited by 1,038 · see citing works
Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine
Hansen, S. G., Ford, J. C., Lewis, M. S., Ventura, A. B., Hughes, C. M., Coyne-Johnson, L., Whizin, N., Oswald, K. A., Shoemaker, R. S., Swanson, T., et al. (2011) · Nature · doi:10.1038/nature10003 · Cited by 989 · see citing works
Similarities and differences in CD4+ and CD8+ effector and memory T cell generation
Seder, R. A., & Ahmed, R. (2003) · Nature Immunology · doi:10.1038/ni969 · Cited by 886 · see citing works
Self-citationMemory CD8 T-Cell Differentiation during Viral Infection
Wherry, E. J., & Ahmed, R. (2004) · Journal of Virology · doi:10.1128/jvi.78.11.5535-5545.2004 · Cited by 858 · see citing works
Self-citationModulation of Chromatin Structure Regulates Cytokine Gene Expression during T Cell Differentiation
Agarwal, S., & Rao, A. (1998) · Immunity · doi:10.1016/s1074-7613(00)80642-1 · Cited by 687 · see citing works
Epigenetic control of T-helper-cell differentiation
Wilson, C. B., Rowell, E. A., & Sekimata, M. (2009) · Nature reviews. Immunology · doi:10.1038/nri2487 · Cited by 678 · see citing works
Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates
Sarkar, S., Kalia, V., Haining, W. N., Konieczny, B. T., Subramaniam, S., & Ahmed, R. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071641 · Cited by 633 · see citing works
Self-citationKalia, V., Sarkar, S., Subramaniam, S., Haining, W. N., Smith, K. A., & Ahmed, R. (2010) · Immunity · doi:10.1016/j.immuni.2009.11.010 · Cited by 590 · see citing works
Self-citationEstimating the Precursor Frequency of Naive Antigen-specific CD8 T Cells
Blattman, J. N., Antia, R., Sourdive, D. J. D., Wang, X., Kaech, S. M., Murali‐Krishna, K., Altman, J. D., & Ahmed, R. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20001021 · Cited by 583 · see citing works
Self-citationQuigley, M. M., Pereyra, F., Nilsson, B., Porichis, F., Fonseca, C., Eichbaum, Q. G., Jülg, B. D., Jesneck, J. L., Brosnahan, K., Imam, S., et al. (2010) · Nature Medicine · doi:10.1038/nm.2232 · Cited by 505 · see citing works
Self-citationGolden‐Mason, L., Palmer, B. E., Kassam, N., Townshend‐Bulson, L., Livingston, S., McMahon, B. J., Castelblanco, N., Kuchroo, V. K., Gretch, D. R., & Rosen, H. R. (2009) · Journal of Virology · doi:10.1128/jvi.00639-09 · Cited by 431 · see citing works
Youngblood, B., Oestreich, K. J., Ha, S., Duraiswamy, J., Akondy, R. S., West, E. E., Wei, Z., Lu, P., Austin, J. W., Riley, J. L., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.06.015 · Cited by 418 · see citing works
Self-citationThe cancer epigenome—components and functional correlatesPreprint
Ting, A. H., McGarvey, K. M., & Baylin, S. B. (2006) · Genes & Development · doi:10.1101/gad.1464906 · Cited by 416 · see citing works
Nakamoto, N., Cho, H., Shaked, A., Olthoff, K., Valiga, M. E., Kaminski, M., Gostick, E., Price, D. A., Freeman, G. J., Wherry, E. J., et al. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000313 · Cited by 380 · see citing works
Self-citationHeterogeneity of CD4<sup>+</sup> memory T cells: Functional modules for tailored immunity
Sallusto, F., & Lanzavecchia, A. (2009) · European Journal of Immunology · doi:10.1002/eji.200939722 · Cited by 348 · see citing works
Stimulation History Dictates Memory CD8 T Cell Phenotype: Implications for Prime-Boost Vaccination
Masopust, D., Ha, S., Vezys, V., & Ahmed, R. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.2.831 · Cited by 313 · see citing works
Self-citationModelling T-cell memory by genetic marking of memory T cells in vivo
Jacob, J., & Baltimore, D. (1999) · Nature · doi:10.1038/21208 · Cited by 308 · see citing works
Features of responding T cells in cancer and chronic infection
Kim, P. S., & Ahmed, R. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.02.005 · Cited by 296 · see citing works
Self-citationWirth, T. C., Xue, H., Rai, D., Sabel, J. T., Bair, T., Harty, J. T., & Badovinac, V. P. (2010) · Immunity · doi:10.1016/j.immuni.2010.06.014 · Cited by 263 · see citing works
Memory CD8 T-cell compartment grows in size with immunological experience
Vezys, V., Yates, A. J., Casey, K. A., Lanier, G., Ahmed, R., Antia, R., & Masopust, D. (2008) · Nature · doi:10.1038/nature07486 · Cited by 218 · see citing works
Self-citationYoung, H. A., Ghosh, P., Ye, J., Lederer, J. A., Lichtman, A. H., Gerard, J. R., Penix, L. A., Wilson, C. B., Melvin, A. J., McGurn, M. E., et al. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.153.8.3603 · Cited by 204 · see citing works
Epigenetic Remodeling of the IL-2 and IFN -γ Loci in Memory CD8 T Cells Is Influenced by CD4 T Cells
Northrop, J. K., Thomas, R. M., Wells, A. D., & Shen, H. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.2.1062 · Cited by 203 · see citing works
Rapid Demethylation of the IFN-γ Gene Occurs in Memory but Not Naive CD8 T Cells
Kersh, E. N., Fitzpatrick, D. R., Murali‐Krishna, K., Shires, J., Speck, S. H., Boss, J. M., & Ahmed, R. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.7.4083 · Cited by 189 · see citing works
Self-citationAraki, Y., Fann, M., Wersto, R. P., & Weng, N. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.12.8102 · Cited by 188 · see citing works
Secondary Replicative Function of CD8 + T Cells That Had Developed an Effector Phenotype
Bannard, O., Kraman, M., & Fearon, D. T. (2009) · Science · doi:10.1126/science.1166831 · Cited by 166 · see citing works
Josefowicz, S. Z., Wilson, C. B., & Rudensky, A. Y. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803320 · Cited by 163 · see citing works
Tight Regulation of Memory CD8 T Cells Limits Their Effectiveness during Sustained High Viral Load
West, E., Youngblood, B., Tan, W., Jin, H., Araki, K., Alexe, G., Konieczny, B., Calpe, S., Freeman, G., Terhorst, C., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.05.017 · Cited by 155 · see citing works
Self-citationEstablishment and Persistence of Virus‐Specific CD4+ and CD8+ T Cell Memory
Doherty, P. C., Topham, D. J., & Tripp, R. A. (1996) · Immunological Reviews · doi:10.1111/j.1600-065x.1996.tb00694.x · Cited by 151 · see citing works
T cell immunity in lymphoid and non-lymphoid tissues
Lefrançois, L., & Masopust, D. (2002) · Current Opinion in Immunology · doi:10.1016/s0952-7915(02)00360-6 · Cited by 116 · see citing works
Ghaffari‐Tabrizi‐Wizsy, N., Bauer, B., Villunger, A., Baier-Bitterlich, G., Altman, A., Utermann, G., Überall, F., & Baier, G. (1999) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199901)29:01 · Cited by 108 · see citing works
Diversity in CD8+ T cell differentiation
Parish, I., & Kaech, S. (2009) · Current Opinion in Immunology · doi:10.1016/j.coi.2009.05.008 · Cited by 102 · see citing works
Overview of Cellular Immunotherapy for Patients with Glioblastoma
Vauléon, É., Avril, T., Collet, B., Mosser, J., & Quillien, V. (2010) · Journal of Immunology Research · doi:10.1155/2010/689171 · Cited by 98 · see citing works
Zediak, V. P., Johnnidis, J. B., Wherry, E. J., & Berger, S. L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003741 · Cited by 80 · see citing works
Self-citationImpaired Memory CD8 T Cell Development in the Absence of Methyl-CpG-Binding Domain Protein 2
Kersh, E. N. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.6.3821 · Cited by 49 · see citing works
Making memories that last a lifetime: heritable functions of self-renewing memory CD8 T cells
Youngblood, B., Davis, C. W., & Ahmed, R. (2010) · International Immunology · doi:10.1093/intimm/dxq437 · Cited by 47 · see citing works
Self-citationJuelich, T., Sutcliffe, E. L., Denton, A. E., He, Y., Doherty, P. C., Parish, C. R., Turner, S. T., Tremethick, D. J., & Rao, S. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901522 · Cited by 43 · see citing works
The effector to memory transition of CD4 T cells
McKinstry, K. K., Strutt, T. M., & Swain, S. L. (2007) · Immunologic Research · doi:10.1007/s12026-007-8004-y · Cited by 42 · see citing works
The contribution of epigenetic memory to immunologic memory
Zediak, V. P., Wherry, E. J., & Berger, S. L. (2011) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2011.01.016 · Cited by 41 · see citing works
Self-citationT-cell memory: You must remember this…
Bevan, M. J., & Goldrath, A. W. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00461-9 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Chen, L., Gibbons, D. L., Goswami, S., Cortez, M. A., Ahn, Y., Byers, L. A., Zhang, X., Yi, X., Dwyer, D. W., Lin, W., et al. (2014) · Nature Communications · doi:10.1038/ncomms6241 · Cited by 972 · see citing works
Human memory T cells: generation, compartmentalization and homeostasis
Farber, D. L., Yudanin, N. A., & Restifo, N. P. (2014) · Nature Reviews Immunology · doi:10.1038/nri3567 · Cited by 897 · see citing works
Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity
Prinzing, B., Zebley, C. C., Petersen, C. T., Fan, Y., Anido, A. A., Yi, Z., Nguyen, P., Houke, H., Bell, M., Haydar, D., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abh0272 · Cited by 349 · see citing works
Self-citationBruno, T. C., Ebner, P. J., Moore, B. L., Squalls, O., Waugh, K. A., Eruslanov, E. B., Singhal, S. K., Mitchell, J. D., Franklin, W. A., Merrick, D. T., et al. (2017) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0075 · Cited by 302 · see citing works
Legat, A., Speiser, D. E., Pircher, H., Zehn, D., & Marraco, S. A. F. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00455 · Cited by 248 · see citing works
Inhibitory Receptors Beyond T Cell Exhaustion
Marraco, S. A. F., Neubert, N. J., Verdeil, G., & Speiser, D. E. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00310 · Cited by 242 · see citing works
Differentiation of CD8 memory T cells depends on Foxo1
Michelini, R. H., Doedens, A. L., Goldrath, A. W., & Hedrick, S. Μ. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20130392 · Cited by 228 · see citing works
Youngblood, B., Noto, A., Porichis, F., Akondy, R. S., Ndhlovu, Z. M., Austin, J. W., Bordi, R., Procopio, F. A., Miura, T., Allen, T. M., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1203161 · Cited by 169 · see citing works
Self-citationT-cell aging in rheumatoid arthritis
Weyand, C. M., Yang, Z., & Goronzy, J. J. (2014) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000011 · Cited by 164 · see citing works
The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment
Agresta, L., Hoebe, K. H. N., & Janssen, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02809 · Cited by 151 · see citing works
Solid-Organ Transplantation in Older Adults: Current Status and Future Research
Abecassis, M. M., Bridges, N. D., Clancy, C. J., Dew, M. A., Eldadah, B. A., Englesbe, M. J., Flessner, M. F., Frank, J. C., Friedewald, J. J., Gill, J. S., et al. (2012) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2012.04245.x · Cited by 140 · see citing works
Ng, C. T., Snell, L. M., Brooks, D. G., & Oldstone, M. B. A. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.05.014 · Cited by 100 · see citing works
Epigenetic Manipulation Restores Functions of Defective CD8+ T Cells From Chronic Viral Infection
Zhang, F., Zhou, X., DiSpirito, J. R., Wang, C., Wang, Y., & Shen, H. (2014) · Molecular Therapy · doi:10.1038/mt.2014.91 · Cited by 95 · see citing works
Ashrafizadeh, M., Ang, H. L., Moghadam, E. R., Mohammadi, S., Zarrin, V., Hushmandi, K., Samarghandian, S., Zarrabi, A., Najafi, M., Mohammadinejad, R., et al. (2020) · Biomolecules · doi:10.3390/biom10071040 · Cited by 87 · see citing works
Epigenetic modulation of the immune function
Suárez-Álvarez, B., Raneros, A. B., Ortega, F., & López‐Larrea, C. (2013) · Epigenetics · doi:10.4161/epi.25201 · Cited by 88 · see citing works
Tumor-necrosis factor impairs CD4+ T cell–mediated immunological control in chronic viral infection
Beyer, M., Abdullah, Z., Chemnitz, J. M., Maisel, D., Sander, J., Lehmann, C., Thabet, Y., Shinde, P. V., Schmidleithner, L. M., Köhne, M., et al. (2016) · Nature Immunology · doi:10.1038/ni.3399 · Cited by 83 · see citing works
PD-1 and BTLA and CD8+T-cell “exhaustion” in cancer
Haymaker, C., Wu, R. C. H., Bernatchez, C., & Radvanyi, L. G. (2012) · OncoImmunology · doi:10.4161/onci.20823 · Cited by 83 · see citing works
Evolution and Diversity of Immune Responses during Acute HIV Infection
Kazer, S. W., Walker, B. D., & Shalek, A. K. (2020) · Immunity · doi:10.1016/j.immuni.2020.10.015 · Cited by 75 · see citing works
Rewriting History: Epigenetic Reprogramming of CD8+ T Cell Differentiation to Enhance Immunotherapy
Zebley, C. C., Gottschalk, S. M., & Youngblood, B. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.06.008 · Cited by 69 · see citing works
Self-citationT cell exhaustion and Interleukin 2 downregulation
Balkhi, M. Y., Ma, Q., Ahmad, S., & Junghans, R. P. (2014) · Cytokine · doi:10.1016/j.cyto.2014.11.024 · Cited by 66 · see citing works
Behar, S. M., Carpenter, S. M., Booty, M. G., Barber, D. L., & Jayaraman, P. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.09.003 · Cited by 63 · see citing works
Kis‐Tóth, K., Comte, D., Karampetsou, M. P., Kyttaris, V. C., Kannan, L., Terhorst, C., & Tsokos, G. C. (2015) · Arthritis & Rheumatology · doi:10.1002/art.39410 · Cited by 63 · see citing works
Broadly Reactive Human CD8 T Cells that Recognize an Epitope Conserved between VZV, HSV and EBV
Chiu, C., McCausland, M. M., Sidney, J., Duh, F.-M. C., Rouphael, N., Mehta, A. K., Mulligan, M. J., Carrington, M. N., Wieland, A., Sullivan, N., et al. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004008 · Cited by 46 · see citing works
Self-citationAcute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion–like Phenotype
Erickson, J. J., Wang, L., Wen, S. C., Hastings, A. K., Gilchuk, P., Joyce, S., Shyr, Y., & Williams, J. V. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1403004 · Cited by 47 · see citing works
Popescu, I., Drummond, M., Gama, L., Coon, T. A., Merlo, C. A., Wise, R. A., Clements, J. E., Kirk, G. D., & McDyer, J. F. (2014) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201407-1226oc · Cited by 44 · see citing works
Billingsley, J. M., Rajakumar, P. A., Connole, M., Salisch, N. C., Adnan, S., Kuzmichev, Y. V., Hong, H. S., Reeves, R. K., Kang, H., Li, W., et al. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004740 · Cited by 44 · see citing works
IL-12 Signaling Promotes TET2-Mediated DNA Demethylation During CD8 T Cell Effector Differentiation
Zebley, C. C., Abdelsamed, H. A., Ghoneim, H. E., Alli, S., Brown, C., Haydar, D., Tian, M., Harris, T. L., McGargill, M. A., Krenciute, G., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2021.109796 · Cited by 45 · see citing works
Self-citationGassner, F. J., Zaborsky, N., Neureiter, D., Huemer, M., Melchardt, T., Egle, A., Rebhandl, S., Catakovic, K., Hartmann, T. N., Greil, R., et al. (2014) · Haematologica · doi:10.3324/haematol.2013.098459 · Cited by 40 · see citing works
Jin, C., Cheng, L., Höxtermann, S., Xie, T., Lu, X.-R., Wu, H., Skaletz‐Rorowski, A., Brockmeyer, N. H., & Wu, N. (2016) · HIV Medicine · doi:10.1111/hiv.12470 · Cited by 39 · see citing works
de Moura, R. G., Covre, L. P., Fantecelle, C. H., Gajardo, V. A. T., Cunha, C. B., Stringari, L. L., Belew, A. T., Daniel, C. B., von Zeidler, S. V., Tadokoro, C. E., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.632667 · Cited by 39 · see citing works
Generating long‐lived CD8+ T‐cell memory: Insights from epigenetic programs
Dogra, P., Ghoneim, H. E., Abdelsamed, H. A., & Youngblood, B. (2016) · European Journal of Immunology · doi:10.1002/eji.201545550 · Cited by 37 · see citing works
Self-citationInhibitory Immune Checkpoint Receptors and Ligands as Prognostic Biomarkers in COVID-19 Patients
Al-Mterin, M. A., Alsalman, A., & Elkord, E. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.870283 · Cited by 34 · see citing works
Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?
Sáez‐Cirión, A., Jacquelin, B., Barré‐Sinoussi, F., & Müller-Trutwin, M. C. (2014) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2013.0436 · Cited by 32 · see citing works
T cell vaccinology: Exploring the known unknowns
Burchill, M. A., Tamburini, B. A. J., Pennock, N. D., White, J. T., Kurche, J. S., & Kedl, R. M. (2012) · Vaccine · doi:10.1016/j.vaccine.2012.10.096 · Cited by 32 · see citing works
Regulation of Antiviral CD8 T-Cell Responses
Kulinski, J. M., Tarakanova, V. L., & Verbsky, J. W. (2013) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.2013007909 · Cited by 30 · see citing works
Lécuroux, C., Girault, I., Chéret, A., Versmisse, P., Nembot, G., Meyer, L., Rouzioux, C., Pancino, G., Venet, A., & Sáez‐Cirión, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059767 · Cited by 25 · see citing works
Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice
Schutt, S. D., Wu, Y., Tang, C.-H. A., Bastian, D. A., Nguyen, H. D., Sofi, M. H., Zhang, M., Liu, C., Helke, K. L., Wilson, C. L., et al. (2018) · Blood Advances · doi:10.1182/bloodadvances.2017009068 · Cited by 26 · see citing works
Immunologic Aging in Adults with Congenital Heart Disease: Does Infant Sternotomy Matter?
Elder, R. W., George, R. P., McCabe, N. M., Rodriguez, F. H., Book, W., Mahle, W. T., & Kirk, A. D. (2015) · Pediatric Cardiology · doi:10.1007/s00246-015-1174-9 · Cited by 25 · see citing works
Asynchronous aging and turnover of human circulating and tissue-resident memory T cells across sites
Lam, N., Angel, J. C., Buchholz, B. A., Lee, Y. S., Weisberg, S. P., Hampton, B. K., Davis‐Porada, J., Caron, D. P., Jensen, I. J., Szabo, P. A., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.07.001 · Cited by 26 · see citing works
Anmole, G., Kuang, X. T., Toyoda, M., Martin, E., Shahid, A., Le, A. Q., Markle, T. J., Baraki, B., Jones, R. B., Ostrowski, M., et al. (2015) · Journal of Immunological Methods · doi:10.1016/j.jim.2015.08.010 · Cited by 22 · see citing works
Simultaneous TCR and CD244 Signals Induce Dynamic Downmodulation of CD244 on Human Antiviral T Cells
Pacheco, Y., McLean, A. P., Rohrbach, J., Porichis, F., Kaufmann, D., & Kavanagh, D. G. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300435 · Cited by 22 · see citing works
Asymptomatic memory CD8+ T cells
Khan, A. A., Srivastava, R., Lopes, P. P., Wang, C., Pham, T. T., Cochrane, J., Thai, N., Gutierrez, L., & BenMohamed, L. (2014) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.27762 · Cited by 17 · see citing works
Popescu, I., Drummond, M., Gama, L., Lambert, A., Hoji, A., Coon, T. A., Merlo, C. A., Wise, R. A., Keruly, J. C., Clements, J. E., et al. (2016) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiw422 · Cited by 21 · see citing works
Kløverpris, H. N., McGregor, R., McLaren, J. E., Ladell, K., Stryhn, A., Koofhethile, C. K., Brener, J., Chen, F., Riddell, L., Graziano, L., et al. (2014) · AIDS · doi:10.1097/qad.0000000000000362 · Cited by 14 · see citing works
Peptide–MHC multimer-based monitoring of CD8 T-cells in HIV-1 infection and AIDS vaccine development
Reguzova, A., Карпенко, Л. И., Mechetina, L. V., & Belyakov, I. M. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2015.962520 · Cited by 12 · see citing works
DC immunotherapy in HIV-1 infection induces a major blood transcriptome shift
de Goede, A. L., Andeweg, A. C., van den Ham, H., Bijl, M., Zaaraoui‐Boutahar, F., van IJcken, W. F. J., Wilgenhof, S., Aerts, J. L., Gruters, R. A., Osterhaus, A. D. M. E., et al. (2015) · Vaccine · doi:10.1016/j.vaccine.2015.04.047 · Cited by 12 · see citing works
Flerin, N. C., Chen, H., Glover, T. D., Lamothe, P. A., Zheng, J. H., Fang, J. W., Ndhlovu, Z. M., Newell, E. W., Davis, M. M., Walker, B. D., et al. (2017) · Journal of Virology · doi:10.1128/jvi.02412-16 · Cited by 11 · see citing works
Yamada, M., Macedo, C., Louis, K., Shi, T., Landsittel, D. P., Nguyen, C., Shinjoh, M., Michaels, M. G., Feingold, B., Mazariegos, G. V., et al. (2023) · American Journal of Transplantation · doi:10.1016/j.ajt.2023.05.007 · Cited by 11 · see citing works
Immunological strategies to target HIV persistence
Martrus, G., & Altfeld, M. A. (2016) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0000000000000289 · Cited by 9 · see citing works
George, M. D., Hu, W. K., Billingsley, J. M., Reeves, R. K., Sankaran‐Walters, S., Johnson, R. P., & Dandekar, S. (2014) · Virology · doi:10.1016/j.virol.2014.09.013 · Cited by 5 · see citing works
Alterations in the CD56− and CD56+ T Cell Subsets during COVID-19
Vavilova, J. D., Ustiuzhanina, M. O., Boyko, A. A., Streltsova, M. A., Kust, S. A., Kanevskiy, L. M., Iskhakov, R. N., Sapozhnikov, A. M., Gubernatorova, E. O., Drutskaya, M. S., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24109047 · Cited by 5 · see citing works
Peptide-Based Therapeutic Cancer Vaccines
Melief, C. J. M. (2017) · Springer eBooks · doi:10.1007/978-3-319-62431-0_14 · Cited by 5 · see citing works
The Nuclear Receptor NR1B1/RARα Arrests the Differentiation of Anti‐Tumor Effector Cytotoxic T Cells
Niekamp, P., Kim, R., Jayaraman, A., Klement, N., Kostlan, R., & Kim, C. H. (2025) · Advancement of science · doi:10.1002/advs.202410241 · Cited by 5 · see citing works
Okarska‐Napierała, M., Woźniak, W., Mańdziuk, J., Ludwikowska, K. M., Feleszko, W., Grzybowski, J., Pańczyk, M., Berdej-Szczot, E., Zaryczański, J., Górnicka, B., et al. (2024) · The Pediatric Infectious Disease Journal · doi:10.1097/inf.0000000000004264 · Cited by 3 · see citing works
Smith, K. N., Mailliard, R. B., & Rinaldo, C. R. (2015) · Forum on Immunopathological Diseases and Therapeutics · doi:10.1615/forumimmundisther.2016014160 · Cited by 3 · see citing works
"Exercising" an alternative viewpoint
Haymaker, C., Wu, R. C. H., Bernatchez, C., & Radvanyi, L. G. (2012) · Cited by 1 · see citing works
IL-12 Signaling Promotes TET2-Mediated DNA Demethylation During CD8 T Cell Effector DifferentiationPreprint
Zebley, C. C., Abdelsamed, H. A., Ghoneim, H. E., Alli, S., Haydar, D., Harris, T. L., McGargill, M. A., Krenciute, G., & Youngblood, B. (2020) · SSRN Electronic Journal · doi:10.2139/ssrn.3720007 · Cited by 1 · see citing works
Self-citationOkarska‐Napierała, M., Woźniak, W., Mańdziuk, J., Ludwikowska, K. M., Feleszko, W., Grzybowski, J., Pańczyk, M., Berdej-Szczot, E., Zaryczański, J., Górnicka, B., et al. (2022) · medRxiv · doi:10.1101/2022.11.02.22281838 · Cited by 1 · see citing works
Ornaghi, A. P. (2013) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Leon-Flores (2012) · American Journal of Infectious Diseases · doi:10.3844/ajidsp.2012.149.162
Reversing T Cell Dysfunction for Tumor Immunotherapy
Kane, L., & Delgoffe, G. M. (2016) · Springer eBooks · doi:10.1007/978-3-319-29827-6_5
The T Cell Co-stimulatory Molecule GITR in the Control and Treatment of a Persistent Viral Infection
Clouthier, D. (2015) · TSpace (University of Toronto)
Wang, K. C. (2018) · TSpace (University of Toronto)
Scott, A. N. (2019) · ERA: Education and Research Archive (University of Alberta) · doi:10.7939/r3-j47p-0v68
Immunity and Protection against Human Metapneumovirus
Wen, S. C. (2015)
Epigenetic reprogramming in tuberculosis: mechanisms of immune evasion and host-directed therapies
Ding, X., Zhou, C., Shi, J., & Qin, Y. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118010
Context-dependent regulation of cytotoxic T lymphocytes by nuclear receptors
Kim, C. H. (2026) · The Journal of Immunology · doi:10.1093/jimmun/vkag261
- Authors
- Youngblood, B., Wherry, E. J., & Ahmed, R.
- Affiliations
- Emory University (US)
- University of Pennsylvania (US)
- Corresponding author
- Youngblood, Ben
- Venue
- Current Opinion in HIV and AIDS
- Published
- 2012-01
- Volume
- 7
- Issue
- 1
- Pages
- 50-57
- ISSN
- 1746-630X (ISSN-L)
- PMC
- PMC3306172
- OpenAlex
- W1987886529
- Cited by
- 68
- References
- 51
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 6 · 2015: 10 · 2014: 13 · 2013: 11 · 2012: 5
- FWCI
- 0.83
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Current Opinion in HIV and AIDS (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (HHSN266200500030C, AI 082630, AI095608, U19AI083022, P01AI080192, AI078897, AI071309, P01AI078897, R01AI071309, AI 083022, R01AI030048, U01AI095608, U19AI082630)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- CD8+ T cell exhaustion, transcriptional regulation, HIV, chronic viral infection, PD-1, 2B4, T cell receptor signaling, co-inhibitory receptors, epigenetic regulation, gene expression profiling, T cell differentiation
- MeSH terms
- Antigens, Viral, Gene Expression Regulation, HIV, Humans, Immunologic Memory, Transcription, Genetic, CD8-Positive T-Lymphocytes, Gene Expression Profiling
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
