Biology:Trained immunity

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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]

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 showed, 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]

References

  1. ↑ 1.0 1.1 "Defining trained immunity and its role in health and disease". Nature Reviews. Immunology 20 (6): 375–388. June 2020. doi:10.1038/s41577-020-0285-6. PMID 32132681. 
  2. ↑ Aaby, Peter; Roth, Adam; Ravn, Henrik; Napirna, Bitiguida Mutna; Rodrigues, Amabelia; Lisse, Ida Maria; Stensballe, Lone; Diness, Birgitte Rode et al. (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. ↑ "A prime time for trained immunity: innate immune memory in newborns and infants". Neonatology (US National Library of Medicine Introduction Line 6 Netea and colleagues recently coined the term trained immunity) 105 (2): 136–141. 2013. doi:10.1159/000356035. 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'". https://ttxdiscovery.com/#:~:text=Pioneering%20work%20from%20Trained%20Therapeutix,is%20called%20'trained%20immunity. 
  5. ↑ "Trained immunity: a memory for innate host defense". Cell Host & Microbe 9 (5): 355–61. May 2011. doi:10.1016/j.chom.2011.04.006. PMID 21575907. 
  6. ↑ "Trained immunity: A program of innate immune memory in health and disease". Science 352 (6284): aaf1098. April 2016. doi:10.1126/science.aaf1098. PMID 27102489. 
  7. ↑ 7.0 7.1 7.2 "Innate immune memory: An evolutionary perspective". Immunological Reviews 283 (1): 21–40. May 2018. doi:10.1111/imr.12647. PMID 29664574. https://archimer.ifremer.fr/doc/00439/55047/90060.pdf. 
  8. ↑ 8.0 8.1 "Immunological memory: What's in a name?". Immunological Reviews 283 (1): 7–20. May 2018. doi:10.1111/imr.12652. PMID 29664563. http://philsci-archive.pitt.edu/16590/1/Pradeu-DuPasquier_Immunological%20memory_Online%20version.pdf. 
  9. ↑ "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. April 2020. 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. et al. (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. PMID 34711598. 
  11. ↑ Stevens, Natalie E.; van Wolfswinkel, Marjolein; Bao, Winnie; Ryan, Feargal J.; Brook, Byron; Amenyogbe, Nelly; Marshall, Helen S.; Lynn, Miriam A. et al. (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. 
  12. ↑ "Gene-specific control of inflammation by TLR-induced chromatin modifications". Nature 447 (7147): 972–978. June 2007. doi:10.1038/nature05836. PMID 17538624. Bibcode: 2007Natur.447..972F. 
  13. ↑ "Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes". Cell Host & Microbe 12 (2): 223–232. August 2012. doi:10.1016/j.chom.2012.06.006. PMID 22901542. 
  14. ↑ "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. June 2013. doi:10.1016/j.micinf.2013.03.002. PMID 23518266. 
  15. ↑ "Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection". Journal of Neuroinflammation 11 (1): 14. January 2014. doi:10.1186/1742-2094-11-14. PMID 24456653. 
  16. ↑ 16.0 16.1 "The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases". Seminars in Immunology 28 (4): 343–350. August 2016. 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. https://www.todayinscience.com/2020/09/01/landmark-trial-shows-trained-immunity-reduces-respiratory-infections-in-the-elderly-by-80/. 
  18. ↑ "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. September 2020. doi:10.1093/cvr/cvaa137. PMID 32396608. 
  19. ↑ "Induction of memory-like dendritic cell responses in vivo". Nature Communications 10 (1): 2955. July 2019. doi:10.1038/s41467-019-10486-5. PMID 31273203. Bibcode: 2019NatCo..10.2955H. 
  20. ↑ "Trained Immunity Contribution to Autoimmune and Inflammatory Disorders". Frontiers in Immunology 13: 868343. 2022. doi:10.3389/fimmu.2022.868343. PMID 35464438. 
  21. ↑ "Trained immunity: A Yin-Yang balance". MedComm 3 (1): e121. 2022. doi:10.1002/mco2.121. PMID 35281787. 
  22. ↑ "Adaptive immune features of natural killer cells". Nature 457 (7229): 557–561. January 2009. doi:10.1038/nature07665. PMID 19136945. Bibcode: 2009Natur.457..557S. 
  23. ↑ "Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection". The Journal of Experimental Medicine 211 (13): 2669–2680. December 2014. doi:10.1084/jem.20141172. PMID 25422494. 
  24. ↑ "IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion". The Journal of Clinical Investigation 124 (12): 5305–5316. December 2014. doi:10.1172/JCI77440. PMID 25384219. 
  25. ↑ "Succinate is an inflammatory signal that induces IL-1β through HIF-1α". Nature 496 (7444): 238–242. April 2013. doi:10.1038/nature11986. PMID 23535595. Bibcode: 2013Natur.496..238T. 
  26. ↑ "Adaptive immune features of natural killer cells". Nature 457 (7229): 557–561. January 2009. doi:10.1038/nature07665. PMID 19136945. Bibcode: 2009Natur.457..557S. 
  27. ↑ "Genital HSV-2 infection induces short-term NK cell memory". PLOS ONE 7 (3): e32821. 2012-03-22. doi:10.1371/journal.pone.0032821. PMID 22457721. Bibcode: 2012PLoSO...732821A. 
  28. ↑ "Influenza vaccine induces intracellular immune memory of human NK cells". PLOS ONE 10 (3): e0121258. 2015-03-17. doi:10.1371/journal.pone.0121258. PMID 25781472. Bibcode: 2015PLoSO..1021258D. 
  29. ↑ "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. September 2011. doi:10.1111/j.1365-2567.2011.03464.x. PMID 21711347. 
  30. ↑ "Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12". Nature Immunology 20 (8): 1004–1011. August 2019. doi:10.1038/s41590-019-0430-1. PMID 31263280. 
  31. ↑ "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. December 2019. doi:10.4049/jimmunol.1801525. PMID 31604804. 
  32. ↑ "Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments". Nature Genetics 51 (1): 138–150. January 2019. doi:10.1038/s41588-018-0298-2. PMID 30531872. https://hal.science/hal-04143430/file/s41588-018-0298-2%20%282%29.pdf. 
  33. ↑ "Proinflammatory cytokine signaling required for the generation of natural killer cell memory". The Journal of Experimental Medicine 209 (5): 947–954. May 2012. doi:10.1084/jem.20111760. PMID 22493516. 
  34. ↑ "Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses". Science Immunology 2 (18): eaan3796. December 2017. doi:10.1126/sciimmunol.aan3796. PMID 29222089. 
  35. ↑ "mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity". Science 345 (6204): 1250684. September 2014. doi:10.1126/science.1250684. PMID 25258083. 
  36. ↑ "Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity". Cell Metabolism 24 (6): 807–819. December 2016. doi:10.1016/j.cmet.2016.10.008. PMID 27866838. 



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