Immunological Memory


Immunological memory is a distinct characteristic of the immune system. This property provides an advantage in the course of protective responses against pathogens and tumour cells. The concept of immunologic memory classically refers to the property of the adaptive branch of the immune system and was described as the development of a response against the same antigen that is greater and faster than the original response. However, there exist two additional types of immunity: transmissible neonatal memory and innate memory or trained immunity. Considerable progress has been made in the elucidation of the multiple cellular and molecular mechanisms regulating the induction and maintenance of immunological memory. Although our understanding remains imperfect, the current cumulative information allows one to recognise operational patterns and identify those principles that will aid better understand the role of the immune system in protection against disease and in the design of better vaccines.

Key Concepts

  • Immunological memory represents an important aspect of the immune system in mammals.
  • Transmissible neonatal memory refers to antibodies transmitted from mother to newborn which protect against cytopathic and life‐threatening pathogens.
  • Classical immunological memory is an acquired property of the adaptive branch of the immune system and involves both B lymphocytes (antibody‐producing cells) and T cells.
  • Innate immunologic memory or trained immunity is a form of immunologic memory that relates to the innate branch of the immune system and involves monocytes, macrophages and natural killer (NK) cells.
  • Memory responses by the immune system occur according to only partially understood operational principles.
  • Memory responses form the basis for the effectiveness of vaccines against pathogens and cancer cells.
  • Memory responses protect the individual and the species against the threat of pathogens and cancer cells.

Keywords: immunological memory; B cells; T cells; germinal centre; memory B cells; effector memory T cells; central memory T cells; stem cell‐like memory T cells; memory antibody response; protection; trained immunity

Figure 1. Dynamic view of the generation of memory B lymphocytes following the germinal centre (GC) reaction. CD45RO (RO) and CD45RO+ (RO+) lymphocytes in GC are seen in relationship with somatic hypermutation. An inverse relationship exists for RO and RO+ B lymphocytes with respect to AID activity and cell proliferation (Ki67 positivity), whereas CD69 positivity (activation) increases as cells become RO+. Memory (M) B cells derive from RO+ cells.
Figure 2. Schematic representation of the two main phases of the primary expansion leading into a long‐term response waiting to re‐encounter antigen. Programming and post‐programming phases, and their relationship with maintenance and homeostatic proliferation are shown.
Figure 3. Development and persistence of serum antibody, and generation and maintenance of immunological memory following one dose of noninfectious poliovirus vaccine. Source: From Zanetti M, Sercarz E, Salk J. The immunology of new generation vaccines. Immunol Today. ;8:18–25. © 1987 Elsevier.


Agrawal B (2019) Heterologous immunity: role in natural and vaccine‐induced resistance to infections. Frontiers in Immunology 10: 2631.

Akbar AN, Beverley PC and Salmon M (2004) Will telomere erosion lead to a loss of T‐cell memory? Nature Reviews. Immunology 4 (9): 737–743.

Almanza G, Fernandez A, Volinia S, et al. (2010) Selected microRNAs define cell fate determination of murine central memory CD8 T cells. PLoS One 5 (6): e11243.

Ariotti S, Hogenbirk MA, Dijkgraaf FE, et al. (2014) T cell memory. Skin‐resident memory CD8(+) T cells trigger a state of tissue‐wide pathogen alert. Science 346 (6205): 101–105.

Arpin C, Banchereau J and Liu YJ (1997) Memory B cells are biased towards terminal differentiation: a strategy that may prevent repertoire freezing. Journal of Experimental Medicine 186 (6): 931–940.

Ataide MA, Andrade WA, Zamboni DS, et al. (2014) Malaria‐induced NLRP12/NLRP3‐dependent caspase‐1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathogens 10 (1): e1003885.

Badovinac VP, Messingham KA, Jabbari A, Haring JS and Harty JT (2005) Accelerated CD8+ T‐cell memory and prime‐boost response after dendritic‐cell vaccination. Nature Medicine 11 (7): 748–756.

Bernasconi NL, Traggiai E and Lanzavecchia A (2002) Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298 (5601): 2199–2202.

Clark EA and Ledbetter JA (1994) How B and T cells talk to each other. Nature 367 (6462): 425–428.

Crotty S (2011) Follicular helper CD4 T cells (TFH). Annual Review of Immunology 29: 621–663. DOI: 10.1146/annurev‐immunol‐031210‐101400.

Cui W and Kaech SM (2010) Generation of effector CD8+ T cells and their conversion to memory T cells. Immunological Reviews 236: 151–166. DOI: 10.1111/j.1600‐065X.2010.00926.x.

Darrah PA, Zeppa JJ, Maiello P, et al. (2020) Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature 577 (7788): 95–102.

Gallimore A, Glithero A, Godkin A, et al. (1998) Induction and exhaustion of lymphocytic choriomeningitis virus‐specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I‐peptide complexes. The Journal of Experimental Medicine 187 (9): 1383–1393.

Gattinoni L, Zhong XS, Palmer DC, et al. (2009) Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature Medicine 15 (7): 808–813.

Gattinoni L, Speiser DE, Lichterfeld M and Bonini C (2017) T memory stem cells in health and disease. Nature Medicine 23 (1): 18–27.

Germain RN, Robey EA and Cahalan MD (2012) A decade of imaging cellular motility and interaction dynamics in the immune system. Science 336 (6089): 1676–1681.

Goldrath AW, Sivakumar PV, Glaccum M, et al. (2002) Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. The Journal of Experimental Medicine 195 (12): 1515–1522.

Gray D and Matzinger P (1991) T cell memory is short‐lived in the absence of antigen. The Journal of Experimental Medicine 174 (5): 969–974.

Hamada A, Torre C, Drancourt M and Ghigo E (2018) Trained immunity carried by non‐immune cells. Frontiers in Microbiology 9: 3225.

Jackson SM, Harp N, Patel D, et al. (2007) CD45RO enriches for activated, highly mutated human germinal center B cells. Blood 110 (12): 3917–3925.

Jacob J and Baltimore D (1999) Modelling T‐cell memory by genetic marking of memory T cells in vivo. Nature 399 (6736): 593–597.

Janssen EM, Lemmens EE, Wolfe T, et al. (2003) CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421 (6925): 852–856.

Kaech SM and Ahmed R (2001) Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nature Immunology 2 (5): 415–422.

Kaech SM, Wherry EJ and Ahmed R (2002) Effector and memory T‐cell differentiation: implications for vaccine development. Nature Reviews. Immunology 2 (4): 251–262.

Kleinnijenhuis J, Quintin J, Preijers F, et al. (2012) Bacille Calmette‐Guerin induces NOD2‐dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proceedings of the National Academy of Sciences of the United States of America 109 (43): 17537–17542.

Lam KP, Kuhn R and Rajewsky K (1997) In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death [see comments]. Cell 90 (6): 1073–1083.

Lanzavecchia A, Bernasconi N, Traggiai E, et al. (2006) Understanding and making use of human memory B cells. Immunological Reviews 211: 303–309.

Lau LL, Jamieson BD, Somasundaram T and Ahmed R (1994) Cytotoxic T‐cell memory without antigen. Nature 369 (6482): 648–652.

Manjunath N, Shankar P, Wan J, et al. (2001) Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. The Journal of Clinical Investigation 108 (6): 871–878.

Mankad R (2015) Atherosclerotic vascular disease in the autoimmune rheumatologic patient. Current Atherosclerosis Reports 17 (4): 497.

Markiewicz MA, Girao C, Opferman JT, et al. (1998) Long‐term T cell memory requires the surface expression of self‐ peptide/major histocompatibility complex molecules. Proceedings of the National Academy of Sciences of the United States of America 95 (6): 3065–3070.

Masopust D, Choo D, Vezys V, et al. (2010) Dynamic T cell migration program provides resident memory within intestinal epithelium. The Journal of Experimental Medicine 207 (3): 553–564.

Masopust D and Soerens AG (2019) Tissue‐resident T cells and other resident leukocytes. Annual Review of Immunology 37: 521–546.

Monticelli S and Natoli G (2013) Short‐term memory of danger signals and environmental stimuli in immune cells. Nature Immunology 14 (8): 777–784.

Morabito KM, Ruckwardt TR, Redwood AJ, et al. (2017) Intranasal administration of RSV antigen‐expressing MCMV elicits robust tissue‐resident effector and effector memory CD8+ T cells in the lung. Mucosal Immunology 10 (2): 545–554.

Murali‐Krishna K, Altman JD, Suresh M, et al. (1998) Counting antigen‐specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8 (2): 177–187.

Netea MG, Joosten LA, Latz E, et al. (2016) Trained immunity: a program of innate immune memory in health and disease. Science 352 (6284): aaf1098.

Redelman‐Sidi G, Glickman MS and Bochner BH (2014) The mechanism of action of BCG therapy for bladder cancer‐‐a current perspective. Nature Reviews. Urology 11 (3): 153–162.

Sanz I, Wei C, Lee FE and Anolik J (2008) Phenotypic and functional heterogeneity of human memory B cells. Seminars in Immunology 20 (1): 67–82.

Schenkel JM, Fraser KA, Vezys V and Masopust D (2013) Sensing and alarm function of resident memory CD8(+) T cells. Nature Immunology 14 (5): 509–513.

Schenkel JM and Masopust D (2014) Tissue‐resident memory T cells. Immunity 41 (6): 886–897.

Sun JC, Beilke JN and Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457 (7229): 557–561.

Szabo PA, Miron M and Farber DL (2019) Location, location, location: tissue resident memory T cells in mice and humans. Science Immunology 4 (34).

Tanchot C, Lemonnier FA, Perarnau B, Freitas AA and Rocha B (1997) Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276 (5321): 2057–2062.

Tew JG, Phipps RP and Mandel TE (1980) The maintenance and regulation of the humoral response: persisiting antigen and the role of follicular antigen‐binding dendritic cells as accessory cells. Immunological Reviews 53: 175–201.

Wrammert J, Smith K, Miller J, et al. (2008) Rapid cloning of high‐affinity human monoclonal antibodies against influenza virus. Nature 453 (7195): 667–671.

Wu T, Hu Y, Lee YT, et al. (2014) Lung‐resident memory CD8 T cells (TRM) are indispensable for optimal cross‐protection against pulmonary virus infection. Journal of Leukocyte Biology 95 (2): 215–224.

Zanetti M, Sercarz E and Salk J (1987) The immunology of new generation vaccines. Immunology Today 8: 18–25.

Zanetti M, Castiglioni P and Ingulli E (2010) Principles of memory CD8 T‐cells generation in relation to protective immunity. Advances in Experimental Medicine and Biology 684: 108–125.

Zinkernagel RM, Bachmann MF, Kundig TM, et al. (1996) On immunological memory. Annual Review of Immunology 14 (333): 333–367.

Further Reading

Ahmed R and Gray D (1996) Immunological memory and protective immunity: understanding their relation. Science 272: 54–60.

Zanetti M and Franchini G (2006) T cell memory and protective immunity: is more better? Trends in Immunology 27: 511–517.

Zanetti M and Schoenberger S (eds) (2010) Memory T cells. Landes Bioscience Publisher: Austin, TX. ISBN: 978‐1‐4419‐6450‐2.

Crotty S (2011) Follicular helper CD4 T cells (TFH). Annual Review of Immunology 29: 621–663.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Zanetti, Maurizio(Dec 2020) Immunological Memory. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0029227]