Trained immunity

Last updated

Trained immunity is a long-term functional modification of cells in the innate immune system which leads to an altered response to a second unrelated challenge. [1] For example, the BCG vaccine leads to a reduction in childhood mortality caused by unrelated infectious agents. [2] The term "innate immune memory" is sometimes used as a synonym for the term trained immunity [3] [4] which was first coined by Mihai Netea in 2011. [5] The term "trained immunity" is relatively new – immunological memory has previously been considered only as a part of adaptive immunity – and refers only to changes in innate immune memory of vertebrates. [6] [7] This type of immunity is thought to be largely mediated by epigenetic modifications. The changes to the innate immune response may last up to several months, in contrast to the classical immunological memory (which may last up to a lifetime), and is usually unspecific because there is no production of specific antibodies/receptors. [8] Trained immunity has been suggested to possess a transgenerational effect, for example the children of mothers who had also received vaccination against BCG had a lower mortality rate than children of unvaccinated mothers. [9] The BRACE trial is currently assessing if BCG vaccination can reduce the impact of COVID-19 in healthcare workers. [10] Other vaccines are also thought to induce immune training such as the DTPw vaccine. [11]

Contents

Immune cells subject to training

Trained immunity is thought to be largely mediated by functional reprogramming of myeloid cells. [1] One of the first described adaptive changes in macrophages were associated with lipopolysaccharide tolerance, which resulted in the silencing of inflammatory genes. [12] Similarly, Candida albicans and fungal β-glucan trigger changes in monocyte histone methylation, this functional reprogramming eventually provides protection against reinfection. [13] Also, a non-specific manner of protection in training with different microbial ligands was shown, for example treatment with fungal β-glucan induced protection against Staphylococcus aureus infection [14] or CpG oligodeoxynucleotide training protecting against infectious with Escherichia coli . [15]

Evidence of trained immunity is found mainly at monocytes/macrophages and NK cells and, less at γδ T cells and innate lymphoid cells. [16]

Monocytes, macrophages and dendritic cells

Monocytes/macrophages can undergo epigenetic modifications after a ligation of their pattern recognition receptors (PRRs). This ligation prepares these cells for a second encounter with the training pathogen. [16] The secondary response may be heightened not only against the training pathogen, but also against different pathogens whose antigens are recognized by the same PRRs. This effect has been observed when stimulating cells by β-glucan, Candida Albicans, or by vaccination against tuberculosis with a vaccine containing BCG. [17] [7] Monocytes are very short-lived cells; however, the heightened secondary response can be spotted even several months after the primary stimulation. This shows that the immune memory is created at the level of progenitor cells, but so far it is not known how this memory is achieved. [7] Though the epigenetic modification is beneficial to the innate immune system response, it can impair macrophage resolution pathways- promoting unfavorable tissue remodeling at the inflammatory site. [18] Additionally, dendritic cells isolated from mice exposed to Cryptococcus neoformans, manifested an immunological memory response, associated with a strong interferon-γ production after C. neoformans reinfection. [19]

Trained immunity can shift macrophages toward a pro-inflammatory glycolytic M1 phenotype by an Akt/mTor HIF1α dependent pathway, away from the M2 phenotype in which macrophages maintain the Krebs cycle and oxidative phosphorylation [20] [21]

NK cells and innate lymphoid cell

The trained immunity involving NK cells looks more like classic immunological memory, because there is development of at least partially-specific clones of NK cells. These cells have receptors on their surface against the antigens with which they came in contact during the first stimulation. [8] For example, after the encounter with cytomegalovirus, certain clones of NK cells (those that have a Ly49H receptor on their surface) expand and then show signs of immunological memory. [22] Reinfection of memory NK cells in mouse led to an enhanced cytokine production by Ly49H receptor with a more specific response to pathogen. [23] In human NK cells, this is mediated by NKG2C a receptor with a similar function as mouse Ly49H. [24] NK cells are known for their memory specific to different pathogens. The first descriptions of NK memory-like phenotype were made on mouse models with murine cytomegalovirus infections. [25] Other viral infections such as Herpes Simplex Virus [26] or Influenza Virus [27] also induce memory or memory-like responses. Memory or memory-like phenotype can be caused by bacterial phatogens, for example Mycobacterium tuberculosis, [28] or eukaryotic pathogens, for example Toxoplasma gondii. [29]

Another resident cell group 1 innate lymphoid cells (ILC1s) were discovered in liver, which expand after the infection with murine cytomegalovirus and which have manifest transcriptional, phenotypical and epigenetic changes. For the induction of ILC1s, pro-inflammatory cytokine and antigen specificity are critical. [30] Lung specific ILC2 showed memory-like phenotype after allergen exposure [31]

Epigenetic reprogramming

Trained immunity relies on epigenetic reprogramming which leads to a stronger and rapid response to recurrent triggers. There are multiple potential epigenetic mechanisms such as changes in chromatin accessibility, DNA methylation or histone modifications. Long non-coding RNAs (lncRNAs) are also critical to epigenetic reprogramming, such as their role in the assignment of H3K4me3 markers to genome which modulates gene expression. [32] Additionally, transcription factors, including STAT4 [33] and RUNX family transcription factors [34] play a role in the introduction of histone modifications. Cell metabolism is a crucial mediator of trained immunity, for example monocytes trained with β-glucan had an increased aerobic glycolysis. Additionally, priming with β-glucan resulted in epigenetic upregulation of genes involved in glycolysis 1 week later. [35] Subsequently, a cross-talk between glycolysis, glutaminolysis and cholesterol synthesis pathways was demonstrated as essential for trained immunity – β-glucan-triggered monocytes. In addition, accumulation of fumarate, caused by glutamine addition into tricarboxylic acid cycle, led to epigenetic reprogramming similar to β-glucan treatment [36]

Related Research Articles

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function.

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

In biology, immunity is the state of being insusceptible or resistant to a noxious agent or process, especially a pathogen or infectious disease. Immunity may occur naturally or be produced by prior exposure or immunization.

Neuroimmunology is a field combining neuroscience, the study of the nervous system, and immunology, the study of the immune system. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, homeostasis, and response to injuries. A long-term goal of this rapidly developing research area is to further develop our understanding of the pathology of certain neurological diseases, some of which have no clear etiology. In doing so, neuroimmunology contributes to development of new pharmacological treatments for several neurological conditions. Many types of interactions involve both the nervous and immune systems including the physiological functioning of the two systems in health and disease, malfunction of either and or both systems that leads to disorders, and the physical, chemical, and environmental stressors that affect the two systems on a daily basis.

rBCG30 is a prospective Bacillus Calmette-Guérin vaccine against tuberculosis. It is a live vaccine, consisting of BCG, which has been evaluated as a tuberculosis vaccination. It is genetically modified to produce abundant amounts of mycolyl transferase, a 30kDa antigen that has been shown to produce a strong immune response in animals and humans. rBCG30 had been in human clinical trials, but no clinical development has been reported since 2007.

Lymphotoxin is a member of the tumor necrosis factor (TNF) superfamily of cytokines, whose members are responsible for regulating the growth and function of lymphocytes and are expressed by a wide variety of cells in the body.

Chemokine ligands 4 previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the CCL4 gene. CCL4 belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the chromosome 17 was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.

In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. The word "adjuvant" comes from the Latin word adiuvare, meaning to help or aid. "An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens."

<span class="mw-page-title-main">Toll-like receptor 4</span> Cell surface receptor found in humans

Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

<span class="mw-page-title-main">CLEC7A</span> Protein-coding gene in humans

C-type lectin domain family 7 member A or Dectin-1 is a protein that in humans is encoded by the CLEC7A gene. CLEC7A is a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. The encoded glycoprotein is a small type II membrane receptor with an extracellular C-type lectin-like domain fold and a cytoplasmic domain with a partial immunoreceptor tyrosine-based activation motif. It functions as a pattern-recognition receptor for a variety of β-1,3-linked and β-1,6-linked glucans from fungi and plants, and in this way plays a role in innate immune response. Expression is found on myeloid dendritic cells, monocytes, macrophages and B cells. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. This gene is closely linked to other CTL/CTLD superfamily members on chromosome 12p13 in the natural killer gene complex region.

<span class="mw-page-title-main">MARCO</span> Protein-coding gene in the species Homo sapiens

Macrophage receptor with collagenous structure (MARCO) is a protein that in humans is encoded by the MARCO gene. MARCO is a class A scavenger receptor that is found on particular subsets of macrophages. Scavenger receptors are pattern recognition receptors (PRRs) found most commonly on immune cells. Their defining feature is that they bind to polyanions and modified forms of a type of cholesterol called low-density lipoprotein (LDL). MARCO is able to bind and phagocytose these ligands and pathogen-associated molecular patterns (PAMPs), leading to the clearance of pathogens and cell signaling events that lead to inflammation. As part of the innate immune system, MARCO clears, or scavenges, pathogens, which leads to inflammatory responses. The scavenger receptor cysteine-rich (SRCR) domain at the end of the extracellular side of MARCO binds ligands to activate the subsequent immune responses. MARCO expression on macrophages has been associated with tumor development and also with Alzheimer's disease, via decreased responses of cells when ligands bind to MARCO.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

<span class="mw-page-title-main">Jos van der Meer</span> Dutch scientist

Jos W.M. van der Meer is emeritus professor and former chairman at the department of internal medicine of the Radboud University Nijmegen Medical Centre in Nijmegen, Netherlands. He is a member of the Royal Netherlands Academy of Arts and Sciences, of which he was vice president and chairman of the division of natural sciences (2006-2012). He is a member of Academia Europaea. Between 2014 and 2016 he was president of European Academies Science Advisory Council (EASAC). He performs research on cytokines and host defence, chronic fatigue syndrome and hyper-immunoglobulinemia D syndrome (HIDS). He is also active in graphic art and makes cartoons, for example for the Dutch science journal Mediator.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

Immunological memory is the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. Generally, they are secondary, tertiary and other subsequent immune responses to the same antigen. The adaptive immune system and antigen-specific receptor generation are responsible for adaptive immune memory.

<span class="mw-page-title-main">Adaptive NK cell</span> Specialized subtype of cytotoxic lymphocyte

An adaptive natural killer (NK) cell or memory-like NK cell is a specialized natural killer cell that has the potential to form immunological memory. They can be distinguished from cytotoxic NK (cNK) cells by their receptor expression profile and epigenome. Adaptive NK cells are so named for properties which they share with the adaptive immune system. Though adaptive NK cells do not possess antigen specificity, they exhibit dynamic expansions of defined cell subsets, increased proliferation and long-term persistence for up to 3 months in vivo, high IFN-γ production, potent cytotoxic activity upon ex vivo restimulation, and protective memory responses.

Immunometabolism is a branch of biology that studies the interplay between metabolism and immunology in all organisms. In particular, immunometabolism is the study of the molecular and biochemical underpinninngs for i) the metabolic regulation of immune function, and ii) the regulation of metabolism by molecules and cells of the immune system. Further categorization includes i) systemic immunometabolism and ii) cellular immunometabolism. Immunometabolism includes metabolic inflammation:a chronic, systemic, low grade inflammation, orchestrated by metabolic deregulation caused by obesity or aging.

<span class="mw-page-title-main">Mihai Netea</span>

Mihai G. Netea is a Romanian Dutch physician and professor at Radboud University Nijmegen, specialized in infectious disease, immunology, and global health.

References

  1. 1 2 Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, et al. (June 2020). "Defining trained immunity and its role in health and disease". Nature Reviews. Immunology. 20 (6): 375–388. doi:10.1038/s41577-020-0285-6. PMC   7186935 . PMID   32132681.
  2. ↑ Aaby, Peter; Roth, Adam; Ravn, Henrik; Napirna, Bitiguida Mutna; Rodrigues, Amabelia; Lisse, Ida Maria; Stensballe, Lone; Diness, Birgitte Rode; Lausch, Karen Rokkedal; Lund, Najaaraq; Biering-Sørensen, Sofie (2011-07-15). "Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?". The Journal of Infectious Diseases. 204 (2): 245–252. doi: 10.1093/infdis/jir240 . ISSN   1537-6613. PMID   21673035.
  3. ↑ Levy O, Wynn JL (2013). "A prime time for trained immunity: innate immune memory in newborns and infants". Neonatology. 105 (2). US National Library of Medicine Introduction Line 6 Netea and colleagues recently coined the term trained immunity: 136–141. doi:10.1159/000356035. PMC   3946366 . PMID   24356292.
  4. ↑ "Trained Therapeutix Discovery founders Mihai Netea and Leo Joosten have revealed that the innate immune systems also has adaptive characteristics. This de facto innate immune memory is called 'trained immunity'". ttxdiscovery.com. Retrieved 25 November 2022.
  5. ↑ Netea MG, Quintin J, van der Meer JW (May 2011). "Trained immunity: a memory for innate host defense". Cell Host & Microbe. 9 (5): 355–61. doi: 10.1016/j.chom.2011.04.006 . PMID   21575907.
  6. ↑ Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, et al. (April 2016). "Trained immunity: A program of innate immune memory in health and disease". Science. 352 (6284): aaf1098. doi:10.1126/science.aaf1098. PMC   5087274 . PMID   27102489.
  7. 1 2 3 Gourbal B, Pinaud S, Beckers GJ, Van Der Meer JW, Conrath U, Netea MG (May 2018). "Innate immune memory: An evolutionary perspective" (PDF). Immunological Reviews. 283 (1): 21–40. doi:10.1111/imr.12647. PMID   29664574. S2CID   4891922.
  8. 1 2 Pradeu T, Du Pasquier L (May 2018). "Immunological memory: What's in a name?" (PDF). Immunological Reviews. 283 (1): 7–20. doi:10.1111/imr.12652. PMID   29664563. S2CID   4893762.
  9. ↑ Berendsen ML, Øland CB, Bles P, Jensen AK, Kofoed PE, Whittle H, et al. (April 2020). "Maternal Priming: Bacillus Calmette-Guérin (BCG) Vaccine Scarring in Mothers Enhances the Survival of Their Child With a BCG Vaccine Scar". Journal of the Pediatric Infectious Diseases Society. 9 (2): 166–172. doi:10.1093/jpids/piy142. PMID   30715451.
  10. ↑ Pittet, Laure F.; Messina, Nicole L.; Gardiner, Kaya; Orsini, Francesca; Abruzzo, Veronica; Bannister, Samantha; Bonten, Marc; Campbell, John L.; Croda, Julio; Dalcolmo, Margareth; Elia, Sonja (2021-10-28). "BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial)". BMJ Open. 11 (10): e052101. doi:10.1136/bmjopen-2021-052101. ISSN   2044-6055. PMC   8557250 . PMID   34711598.
  11. ↑ Stevens, Natalie E.; van Wolfswinkel, Marjolein; Bao, Winnie; Ryan, Feargal J.; Brook, Byron; Amenyogbe, Nelly; Marshall, Helen S.; Lynn, Miriam A.; Kollmann, Tobias R.; Tumes, Damon J.; Lynn, David J. (2022-03-08). "Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice". Vaccine. 40 (11): 1594–1605. doi:10.1016/j.vaccine.2021.03.084. ISSN   1873-2518. PMID   33895015. S2CID   233399069.
  12. ↑ Foster SL, Hargreaves DC, Medzhitov R (June 2007). "Gene-specific control of inflammation by TLR-induced chromatin modifications". Nature. 447 (7147): 972–978. Bibcode:2007Natur.447..972F. doi:10.1038/nature05836. PMID   17538624. S2CID   4426398.
  13. ↑ Quintin J, Saeed S, Martens JH, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C, et al. (August 2012). "Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes". Cell Host & Microbe. 12 (2): 223–232. doi:10.1016/j.chom.2012.06.006. PMC   3864037 . PMID   22901542.
  14. ↑ Marakalala MJ, Williams DL, Hoving JC, Engstad R, Netea MG, Brown GD (June 2013). "Dectin-1 plays a redundant role in the immunomodulatory activities of β-glucan-rich ligands in vivo". Microbes and Infection. 15 (6–7): 511–515. doi:10.1016/j.micinf.2013.03.002. PMC   3839404 . PMID   23518266.
  15. ↑ Ribes S, Meister T, Ott M, Redlich S, Janova H, Hanisch UK, et al. (January 2014). "Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection". Journal of Neuroinflammation. 11 (1): 14. doi: 10.1186/1742-2094-11-14 . PMC   3906862 . PMID   24456653.
  16. 1 2 Gardiner CM, Mills KH (August 2016). "The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases". Seminars in Immunology. 28 (4): 343–350. doi:10.1016/j.smim.2016.03.001. PMID   26979658.
  17. ↑ "Landmark trial shows trained immunity reduces respiratory infections in the elderly by 80%". Today in Science. Retrieved 2020-09-02.
  18. ↑ Steffens S, Van Linthout S, Sluijter JP, Tocchetti CG, Thum T, Madonna R (September 2020). "Stimulating pro-reparative immune responses to prevent adverse cardiac remodelling: consensus document from the joint 2019 meeting of the ESC Working Groups of cellular biology of the heart and myocardial function". Cardiovascular Research. 116 (11): 1850–1862. doi: 10.1093/cvr/cvaa137 . PMID   32396608.
  19. ↑ Hole CR, Wager CM, Castro-Lopez N, Campuzano A, Cai H, Wozniak KL, et al. (July 2019). "Induction of memory-like dendritic cell responses in vivo". Nature Communications. 10 (1): 2955. Bibcode:2019NatCo..10.2955H. doi:10.1038/s41467-019-10486-5. PMC   6609631 . PMID   31273203.
  20. ↑ Funes SC, Rios M, Kalergis AM (2022). "Trained Immunity Contribution to Autoimmune and Inflammatory Disorders". Frontiers in Immunology . 13: 868343. doi: 10.3389/fimmu.2022.868343 . PMC   9028757 . PMID   35464438.
  21. ↑ Hu Z, Lu S, Lowrie DB, Fan X (2022). "Trained immunity: A Yin-Yang balance". MedComm . 3 (1): e121. doi:10.1002/mco2.121. PMC   8906449 . PMID   35281787.
  22. ↑ Sun JC, Beilke JN, Lanier LL (January 2009). "Adaptive immune features of natural killer cells". Nature. 457 (7229): 557–561. Bibcode:2009Natur.457..557S. doi:10.1038/nature07665. PMC   2674434 . PMID   19136945.
  23. ↑ Min-Oo G, Lanier LL (December 2014). "Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection". The Journal of Experimental Medicine. 211 (13): 2669–2680. doi:10.1084/jem.20141172. PMC   4267234 . PMID   25422494.
  24. ↑ Rölle A, Pollmann J, Ewen EM, Le VT, Halenius A, Hengel H, Cerwenka A (December 2014). "IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion". The Journal of Clinical Investigation. 124 (12): 5305–5316. doi:10.1172/JCI77440. PMC   4348979 . PMID   25384219.
  25. ↑ Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. (April 2013). "Succinate is an inflammatory signal that induces IL-1β through HIF-1α". Nature. 496 (7444): 238–242. Bibcode:2013Natur.496..238T. doi:10.1038/nature11986. PMC   4031686 . PMID   23535595.
  26. ↑ Sun JC, Beilke JN, Lanier LL (January 2009). "Adaptive immune features of natural killer cells". Nature. 457 (7229): 557–561. Bibcode:2009Natur.457..557S. doi:10.1038/nature07665. PMC   2674434 . PMID   19136945.
  27. ↑ Abdul-Careem MF, Lee AJ, Pek EA, Gill N, Gillgrass AE, Chew MV, et al. (2012-03-22). "Genital HSV-2 infection induces short-term NK cell memory". PLOS ONE. 7 (3): e32821. Bibcode:2012PLoSO...732821A. doi: 10.1371/journal.pone.0032821 . PMC   3310819 . PMID   22457721.
  28. ↑ Dou Y, Fu B, Sun R, Li W, Hu W, Tian Z, Wei H (2015-03-17). "Influenza vaccine induces intracellular immune memory of human NK cells". PLOS ONE. 10 (3): e0121258. Bibcode:2015PLoSO..1021258D. doi: 10.1371/journal.pone.0121258 . PMC   4363902 . PMID   25781472.
  29. ↑ Fu X, Liu Y, Li L, Li Q, Qiao D, Wang H, et al. (September 2011). "Human natural killer cells expressing the memory-associated marker CD45RO from tuberculous pleurisy respond more strongly and rapidly than CD45RO- natural killer cells following stimulation with interleukin-12". Immunology. 134 (1): 41–49. doi:10.1111/j.1365-2567.2011.03464.x. PMC   3173693 . PMID   21711347.
  30. ↑ Weizman OE, Song E, Adams NM, Hildreth AD, Riggan L, Krishna C, et al. (August 2019). "Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12". Nature Immunology. 20 (8): 1004–1011. doi:10.1038/s41590-019-0430-1. PMC   6697419 . PMID   31263280.
  31. ↑ Ivanova DL, Mundhenke TM, Gigley JP (December 2019). "The IL-12- and IL-23-Dependent NK Cell Response Is Essential for Protective Immunity against Secondary Toxoplasma gondii Infection". Journal of Immunology. 203 (11): 2944–2958. doi:10.4049/jimmunol.1801525. PMC   6864276 . PMID   31604804.
  32. ↑ Fanucchi S, Fok ET, Dalla E, Shibayama Y, Börner K, Chang EY, et al. (January 2019). "Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments" (PDF). Nature Genetics. 51 (1): 138–150. doi:10.1038/s41588-018-0298-2. PMID   30531872. S2CID   54463671.
  33. ↑ Sun JC, Madera S, Bezman NA, Beilke JN, Kaplan MH, Lanier LL (May 2012). "Proinflammatory cytokine signaling required for the generation of natural killer cell memory". The Journal of Experimental Medicine. 209 (5): 947–954. doi:10.1084/jem.20111760. PMC   3348098 . PMID   22493516.
  34. ↑ Rapp M, Lau CM, Adams NM, Weizman OE, O'Sullivan TE, Geary CD, Sun JC (December 2017). "Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses". Science Immunology. 2 (18): eaan3796. doi:10.1126/sciimmunol.aan3796. PMC   6265048 . PMID   29222089.
  35. ↑ Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. (September 2014). "mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity". Science. 345 (6204): 1250684. doi:10.1126/science.1250684. PMC   4226238 . PMID   25258083.
  36. ↑ Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, et al. (December 2016). "Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity". Cell Metabolism. 24 (6): 807–819. doi:10.1016/j.cmet.2016.10.008. PMC   5742541 . PMID   27866838.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.