Trained immunity

'''Trained immunity''' is a long-term functional modification of chromatin in cells of the innate immune system which leads to an altered response to a second unrelated challenge.<ref name=":3">{{cite journal |vauthors=Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LA, van der Meer JW, Mhlanga MM, Mulder WJ, Riksen NP, Schlitzer A, Schultze JL, Stabell Benn C, Sun JC, Xavier RJ, Latz E |display-authors=6 |title=Defining trained immunity and its role in health and disease |journal=Nature Reviews. Immunology |volume=20 |issue=6 |pages=375–388 |date=June 2020 |pmid=32132681 |pmc=7186935 |doi=10.1038/s41577-020-0285-6}}</ref> For example, the BCG vaccine leads to a reduction in childhood mortality caused by unrelated infectious agents.<ref>{{Cite journal |last1=Aaby |first1=Peter |last2=Roth |first2=Adam |last3=Ravn |first3=Henrik |last4=Napirna |first4=Bitiguida Mutna |last5=Rodrigues |first5=Amabelia |last6=Lisse |first6=Ida Maria |last7=Stensballe |first7=Lone |last8=Diness |first8=Birgitte Rode |last9=Lausch |first9=Karen Rokkedal |last10=Lund |first10=Najaaraq |last11=Biering-Sørensen |first11=Sofie |date=2011-07-15 |title=Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? |journal=The Journal of Infectious Diseases |volume=204 |issue=2 |pages=245–252 |doi=10.1093/infdis/jir240 |issn=1537-6613 |pmid=21673035|doi-access=free }}</ref> The term "innate immune memory" is sometimes used as a synonym for the term ''trained immunity''<ref>{{cite journal |vauthors=Levy O, Wynn JL |year=2013 |title=A prime time for trained immunity: innate immune memory in newborns and infants |journal=Neonatology |publisher=US National Library of Medicine Introduction Line 6 Netea and colleagues recently coined the term trained immunity |volume=105 |issue=2 |pages=136–141 |doi=10.1159/000356035 |pmc=3946366 |pmid=24356292}}</ref><ref>{{cite web |url=https://ttxdiscovery.com/#:~:text=Pioneering%20work%20from%20Trained%20Therapeutix,is%20called%20'trained%20immunity |title=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'|website=ttxdiscovery.com|access-date=25 November 2022}}</ref> which was first coined by Mihai Netea in 2011.<ref name="pmid21575907">{{cite journal |vauthors=Netea MG, Quintin J, van der Meer JW |date=May 2011 |title=Trained immunity: a memory for innate host defense |journal=Cell Host & Microbe |volume=9 |issue=5 |pages=355–61 |doi=10.1016/j.chom.2011.04.006 |pmid=21575907|doi-access=free }}</ref> The term "trained immunity" is relatively new &ndash; immunological memory has previously been considered only as a part of adaptive immunity &ndash; and refers only to changes in innate immune memory of vertebrates.<ref>{{cite journal |display-authors=6 |vauthors=Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O'Neill LA, Xavier RJ |date=April 2016 |title=Trained immunity: A program of innate immune memory in health and disease |journal=Science |volume=352 |issue=6284 |article-number=aaf1098 |doi=10.1126/science.aaf1098 |pmc=5087274 |pmid=27102489}}</ref><ref name=":1">{{cite journal |vauthors=Gourbal B, Pinaud S, Beckers GJ, Van Der Meer JW, Conrath U, Netea MG |date=May 2018 |title=Innate immune memory: An evolutionary perspective |journal=Immunological Reviews |volume=283 |issue=1 |pages=21–40 |doi=10.1111/imr.12647 |pmid=29664574 |s2cid=4891922 |url=https://archimer.ifremer.fr/doc/00439/55047/90060.pdf}}</ref> 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.<ref name=":0">{{cite journal |vauthors=Pradeu T, Du Pasquier L |title=Immunological memory: What's in a name? |journal=Immunological Reviews |volume=283 |issue=1 |pages=7–20 |date=May 2018 |pmid=29664563 |doi=10.1111/imr.12652 |s2cid=4893762 |url=http://philsci-archive.pitt.edu/16590/1/Pradeu-DuPasquier_Immunological%20memory_Online%20version.pdf}}</ref> 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.<ref>{{cite journal |vauthors=Berendsen ML, Øland CB, Bles P, Jensen AK, Kofoed PE, Whittle H, de Bree LC, Netea MG, Martins C, Benn CS, Aaby P |display-authors=6 |title=Maternal Priming: Bacillus Calmette-Guérin (BCG) Vaccine Scarring in Mothers Enhances the Survival of Their Child With a BCG Vaccine Scar |journal=Journal of the Pediatric Infectious Diseases Society |volume=9 |issue=2 |pages=166–172 |date=April 2020 |pmid=30715451 |doi=10.1093/jpids/piy142}}</ref> The BRACE trial is currently assessing if BCG vaccination can reduce the impact of COVID-19 in healthcare workers.<ref>{{Cite journal |last1=Pittet |first1=Laure F. |last2=Messina |first2=Nicole L. |last3=Gardiner |first3=Kaya |last4=Orsini |first4=Francesca |last5=Abruzzo |first5=Veronica |last6=Bannister |first6=Samantha |last7=Bonten |first7=Marc |last8=Campbell |first8=John L. |last9=Croda |first9=Julio |last10=Dalcolmo |first10=Margareth |last11=Elia |first11=Sonja |date=2021-10-28 |title=BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial) |journal=BMJ Open |volume=11 |issue=10 |article-number=e052101 |doi=10.1136/bmjopen-2021-052101 |doi-access=free|issn=2044-6055 |pmc=8557250 |pmid=34711598}}</ref> Other vaccines are also thought to induce immune training such as the DTPw vaccine.<ref>{{Cite journal |last1=Stevens |first1=Natalie E. |last2=van Wolfswinkel |first2=Marjolein |last3=Bao |first3=Winnie |last4=Ryan |first4=Feargal J. |last5=Brook |first5=Byron |last6=Amenyogbe |first6=Nelly |last7=Marshall |first7=Helen S. |last8=Lynn |first8=Miriam A. |last9=Kollmann |first9=Tobias R. |last10=Tumes |first10=Damon J. |last11=Lynn |first11=David J. |date=2022-03-08 |title=Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice |journal=Vaccine |volume=40 |issue=11 |pages=1594–1605 |doi=10.1016/j.vaccine.2021.03.084 |issn=1873-2518 |pmid=33895015 |s2cid=233399069|pmc=12273738 }}</ref>

== Immune cells subject to training == Trained immunity is thought to be largely mediated by functional reprogramming of myeloid cells.<ref name=":3" /> One of the first described adaptive changes in macrophages were associated with lipopolysaccharide tolerance, which resulted in the silencing of inflammatory genes.<ref>{{cite journal |vauthors=Foster SL, Hargreaves DC, Medzhitov R |title=Gene-specific control of inflammation by TLR-induced chromatin modifications |journal=Nature |volume=447 |issue=7147 |pages=972–978 |date=June 2007 |pmid=17538624 |doi=10.1038/nature05836 |bibcode=2007Natur.447..972F |s2cid=4426398}}</ref> Similarly, ''Candida albicans and'' fungal β-glucan trigger changes in monocyte histone methylation, this functional reprogramming eventually provides protection against reinfection.<ref>{{cite journal |vauthors=Quintin J, Saeed S, Martens JH, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C, Jacobs L, Jansen T, Kullberg BJ, Wijmenga C, Joosten LA, Xavier RJ, van der Meer JW, Stunnenberg HG, Netea MG |display-authors=6 |title=Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes |journal=Cell Host & Microbe |volume=12 |issue=2 |pages=223–232 |date=August 2012 |pmid=22901542 |pmc=3864037 |doi=10.1016/j.chom.2012.06.006}}</ref> 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<ref>{{cite journal |vauthors=Marakalala MJ, Williams DL, Hoving JC, Engstad R, Netea MG, Brown GD |title=Dectin-1 plays a redundant role in the immunomodulatory activities of β-glucan-rich ligands in vivo |journal=Microbes and Infection |volume=15 |issue=6–7 |pages=511–515 |date=June 2013 |pmid=23518266 |pmc=3839404 |doi=10.1016/j.micinf.2013.03.002 }}</ref> or CpG oligodeoxynucleotide training protecting against infectious with ''Escherichia coli''.<ref>{{cite journal |vauthors=Ribes S, Meister T, Ott M, Redlich S, Janova H, Hanisch UK, Nessler S, Nau R |display-authors=6 |title=Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection |journal=Journal of Neuroinflammation |volume=11 |issue=1 |page=14 |date=January 2014 |pmid=24456653 |pmc=3906862 |doi=10.1186/1742-2094-11-14 |doi-access=free }}</ref>

Evidence of trained immunity is found mainly at monocytes/macrophages and NK cells and, less at γδ T cells and innate lymphoid cells.<ref name=":2">{{cite journal |vauthors=Gardiner CM, Mills KH |title=The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases |journal=Seminars in Immunology |volume=28 |issue=4 |pages=343–350 |date=August 2016 |pmid=26979658 |doi=10.1016/j.smim.2016.03.001}}</ref>

=== 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.<ref name=":2" /> 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.<ref>{{cite web |url=https://www.todayinscience.com/2020/09/01/landmark-trial-shows-trained-immunity-reduces-respiratory-infections-in-the-elderly-by-80/|title=Landmark trial shows trained immunity reduces respiratory infections in the elderly by 80%|publisher=Today in Science |access-date=2020-09-02}}</ref><ref name=":1" /> 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.<ref name=":1" /> 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.<ref>{{cite journal |vauthors=Steffens S, Van Linthout S, Sluijter JP, Tocchetti CG, Thum T, Madonna R |title=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 |journal=Cardiovascular Research |volume=116 |issue=11 |pages=1850–1862 |date=September 2020 |pmid=32396608 |doi=10.1093/cvr/cvaa137|doi-access=free }}</ref> 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.<ref>{{cite journal |vauthors=Hole CR, Wager CM, Castro-Lopez N, Campuzano A, Cai H, Wozniak KL, Wang Y, Wormley FL |display-authors=6 |title=Induction of memory-like dendritic cell responses in vivo |journal=Nature Communications |volume=10 |issue=1 |article-number=2955 |date=July 2019 |pmid=31273203 |pmc=6609631 |doi=10.1038/s41467-019-10486-5 |bibcode=2019NatCo..10.2955H}}</ref>

Trained immunity can shift macrophages toward a pro-inflammatory glycolytic M1&nbsp;phenotype by an Akt/mTor HIF1α dependent pathway, away from the M2&nbsp;phenotype in which macrophages maintain the Krebs cycle and oxidative phosphorylation<ref name="pmid35464438">{{cite journal |vauthors=Funes SC, Rios M, Kalergis AM |title=Trained Immunity Contribution to Autoimmune and Inflammatory Disorders |journal=Frontiers in Immunology |volume=13 |article-number=868343 |date=2022 |doi=10.3389/fimmu.2022.868343 |pmc=9028757 |pmid=35464438| doi-access=free}}</ref><ref name="pmid35281787">{{cite journal |vauthors=Hu Z, Lu S, Lowrie DB, Fan X |title=Trained immunity: A Yin-Yang balance |journal=MedComm |volume=3 |issue=1 |article-number=e121 |date= 2022 |doi=10.1002/mco2.121 |pmc=8906449 |pmid=35281787}}</ref>

{{Cleanup|reason=citation; too heavy focus on specific people|date=December 2020}}

=== 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.<ref name=":0" /> 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.<ref>{{cite journal |vauthors=Sun JC, Beilke JN, Lanier LL |title=Adaptive immune features of natural killer cells |journal=Nature |volume=457 |issue=7229 |pages=557–561 |date=January 2009 |pmid=19136945 |pmc=2674434 |doi=10.1038/nature07665 |bibcode=2009Natur.457..557S }}</ref> Reinfection of memory NK cells in mouse led to an enhanced cytokine production by Ly49H receptor with a more specific response to pathogen.<ref>{{cite journal |vauthors=Min-Oo G, Lanier LL |title=Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection |journal=The Journal of Experimental Medicine |volume= 211 |issue=13 |pages=2669–2680 |date=December 2014 |pmid=25422494 |pmc=4267234 |doi=10.1084/jem.20141172}}</ref> In human NK cells, this is mediated by NKG2C a receptor with a similar function as mouse Ly49H.<ref>{{cite journal |vauthors=Rölle A, Pollmann J, Ewen EM, Le VT, Halenius A, Hengel H, Cerwenka A |title=IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion |journal= The Journal of Clinical Investigation |volume=124 |issue=12 |pages=5305–5316 |date=December 2014 |pmid=25384219 |pmc=4348979 |doi=10.1172/JCI77440}}</ref> 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.<ref>{{cite journal |vauthors=Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O'Neill LA |display-authors=6 |title=Succinate is an inflammatory signal that induces IL-1β through HIF-1α |journal=Nature |volume=496 |issue=7444 |pages=238–242 |date=April 2013 |pmid=23535595 |pmc=4031686 |doi=10.1038/nature11986 |bibcode=2013Natur.496..238T}}</ref> Other viral infections such as Herpes Simplex Virus<ref>{{cite journal |vauthors=Sun JC, Beilke JN, Lanier LL |title=Adaptive immune features of natural killer cells |journal=Nature |volume=457 |issue=7229 |pages=557–561 |date=January 2009 |pmid=19136945 |pmc=2674434 |doi=10.1038/nature07665 |bibcode=2009Natur.457..557S}}</ref> or Influenza Virus<ref>{{cite journal |vauthors=Abdul-Careem MF, Lee AJ, Pek EA, Gill N, Gillgrass AE, Chew MV, Reid S, Ashkar AA |display-authors=6 |title=Genital HSV-2 infection induces short-term NK cell memory |journal=PLOS ONE |volume=7 |issue=3 |article-number=e32821 |date=2012-03-22 |pmid=22457721 |pmc=3310819 |doi=10.1371/journal.pone.0032821 |bibcode=2012PLoSO...732821A |doi-access=free}}</ref> also induce memory or memory-like responses. Memory or memory-like phenotype can be caused by bacterial phatogens, for example Mycobacterium tuberculosis,<ref>{{cite journal |vauthors=Dou Y, Fu B, Sun R, Li W, Hu W, Tian Z, Wei H |title=Influenza vaccine induces intracellular immune memory of human NK cells |journal=PLOS ONE |volume= 10 |issue=3 |article-number=e0121258 |date=2015-03-17 |pmid=25781472 |pmc=4363902 |doi=10.1371/journal.pone.0121258 |bibcode=2015PLoSO..1021258D |doi-access=free}}</ref> or eukaryotic pathogens, for example Toxoplasma gondii.<ref>{{cite journal |vauthors=Fu X, Liu Y, Li L, Li Q, Qiao D, Wang H, Lao S, Fan Y, Wu C |display-authors=6 |title=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 |journal=Immunology |volume=134 |issue=1 |pages=41–49 |date=September 2011 |pmid=21711347 |pmc=3173693 |doi=10.1111/j.1365-2567.2011.03464.x }}</ref>

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.<ref>{{cite journal |vauthors=Weizman OE, Song E, Adams NM, Hildreth AD, Riggan L, Krishna C, Aguilar OA, Leslie CS, Carlyle JR, Sun JC, O'Sullivan TE |display-authors=6 |title=Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12 |journal=Nature Immunology |volume=20 |issue=8 |pages=1004–1011 |date=August 2019 |pmid=31263280 |pmc=6697419 |doi=10.1038/s41590-019-0430-1 }}</ref> Lung specific ILC2 showed memory-like phenotype after allergen exposure<ref>{{cite journal |vauthors=Ivanova DL, Mundhenke TM, Gigley JP |title=The IL-12- and IL-23-Dependent NK Cell Response Is Essential for Protective Immunity against Secondary ''Toxoplasma gondii'' Infection |journal=Journal of Immunology |volume=203 |issue=11 |pages=2944–2958 |date=December 2019 |pmid=31604804 |pmc=6864276 |doi=10.4049/jimmunol.1801525 }}</ref>

== 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.<ref>{{cite journal |vauthors=Fanucchi S, Fok ET, Dalla E, Shibayama Y, Börner K, Chang EY, Stoychev S, Imakaev M, Grimm D, Wang KC, Li G, Sung WK, Mhlanga MM |display-authors=6 |title=Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments |journal=Nature Genetics |volume=51 |issue=1 |pages=138–150 |date=January 2019 |pmid=30531872 |doi=10.1038/s41588-018-0298-2 |s2cid=54463671|url=https://hal.science/hal-04143430/file/s41588-018-0298-2%20%282%29.pdf }}</ref> Additionally, transcription factors, including STAT4<ref>{{cite journal |vauthors=Sun JC, Madera S, Bezman NA, Beilke JN, Kaplan MH, Lanier LL |title=Proinflammatory cytokine signaling required for the generation of natural killer cell memory |journal=The Journal of Experimental Medicine |volume=209 |issue=5 |pages=947–954 |date=May 2012 |pmid=22493516 |pmc=3348098 |doi=10.1084/jem.20111760}}</ref> and RUNX family transcription factors<ref>{{cite journal |vauthors=Rapp M, Lau CM, Adams NM, Weizman OE, O'Sullivan TE, Geary CD, Sun JC |title=Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses |journal=Science Immunology |volume=2 |issue=18 |article-number=eaan3796 |date=December 2017 |pmid=29222089 |pmc=6265048 |doi=10.1126/sciimmunol.aan3796 }}</ref> 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.<ref>{{cite journal |vauthors=Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, Giamarellos-Bourboulis EJ, Martens JH, Rao NA, Aghajanirefah A, Manjeri GR, Li Y, Ifrim DC, Arts RJ, van der Veer BM, van der Meer BM, Deen PM, Logie C, O'Neill LA, Willems P, van de Veerdonk FL, van der Meer JW, Ng A, Joosten LA, Wijmenga C, Stunnenberg HG, Xavier RJ, Netea MG |display-authors=6 |title=mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity |journal=Science |volume=345 |issue=6204 |article-number=1250684 |date=September 2014 |pmid=25258083 |pmc=4226238 |doi=10.1126/science.1250684}}</ref> 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<ref>{{cite journal |vauthors=Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, Rodrigues F, Silvestre R, Cheng SC, Wang SY, Habibi E, Gonçalves LG, Mesquita I, Cunha C, van Laarhoven A, van de Veerdonk FL, Williams DL, van der Meer JW, Logie C, O'Neill LA, Dinarello CA, Riksen NP, van Crevel R, Clish C, Notebaart RA, Joosten LA, Stunnenberg HG, Xavier RJ, Netea MG |display-authors=6 |title=Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity |journal=Cell Metabolism |volume=24 |issue=6 |pages=807–819 |date=December 2016 |pmid=27866838 |pmc=5742541 |doi=10.1016/j.cmet.2016.10.008 }}</ref>

== References == {{Reflist}}

Category:Immunology