Immunological memory

Immunological memory is a specific memory function of the immune system. In simple terms, acquired immune memory enables the organism to develop a secondary immune response through various immunological reactions organized in the primary immune response (Netea MG et al. 2017). In this process the cells involved also undergo epigenetic changes (Kondilis-Mangum HD et al. 2013). The immune system thus reacts flexibly and dynamically to antigens of the environment, retains its memory of previous antigens and recalls the acquired memory function when required.

The first suitable contact with a pathogen (allergen) triggers a primary immune response in the organism. In case of a second contact with the same antigen, the immune system is now able to react stronger and faster than in case of first contact due to its memory function, often with little or even no alarm by danger signals.

In general, 2 mechanisms are cited as explanations for the existence and function of the immunological memory:

• the antigen persists in the organism after an immune response, and constitutes a permanent immunological stimulus
• the antigen contact leads to the formation of long-lived memory cells, which become effector cells on second contact with the antigen.

It is known, for example, that immunizations (e.g. in vaccinations) against some pathogens (allergens) are only required once during a lifetime. For other pathogens (allergens), however, vaccination boosters (memory reactions) are necessary.

For the shorter immunological memory, the persistence of the antigen in lymph nodes seems to be important (affinity maturation). There, the antigen in the lymph follicles is bound by the follicular dendritic cells into antigen-antibody complexes (immune complexes). From these immune complexes the antigen is slowly released and thus forms a permanent stimulus for the immune system.

The special mechanism of antigen presentation (immunological synapse) during stimulation of naïve T cells seems to play a role in the longer immunological memory (Vukmanovic-Stejic M et al. 2006). A naïve T cell is a resting T cell that has not yet had antigen contact and therefore has no immunological memory (Quintin J et al. 2014). On its cell membrane surface there are about 25,000 TCR (T-cell receptors) distributed individually. The act of sensitization requires close communication between an antigen-presenting cell (APZ) and the T-lymphocyte. The APZ presents antigen fragments on the MHC class I molecules of the T-cell, which it stimulates to divide.

In the memory T cells formed by the initial antigen contact, the same T cell receptors are now pre-grouped into several clusters. If an antigen were to hit a naive T cell, only a single TCR would be stimulated. For an immune response, however, this stimulation is not sufficient to exceed the critical threshold value necessary for a specific immune response. It has been shown that in memory cells TCRs accumulate to form nanoclusters (Beck-García K et al. 2015). A single antigen is now sufficient to stimulate the entire cluster. Thus, the concentration of the allergen can be comparatively low to induce a specific immune response. Remarkably, the degree of TCR nanoclustering and thus the sensitivity of the T cells is influenced by the membrane lipid composition of the cell surface as well as by LDL cholesterol of the serum. If cholesterol is extracted from the cells, the cluster disintegrates again into individual receptors. The cells lose their high sensitivity (Christ A et al. 2016)

Furthermore, a special feature must be taken into account, namely the low specificity of the MHC molecules. This special feature leads to the fact that not only the immunizing antigen or its fragments are recognized and presented, but also antigen fragments which do not show direct sequence homology with the original antigen. Thus, an immune response against a defined allergen (e.g. virus 1) can be induced experimentally by immunization with another immunologically heterogeneous antigen (e.g. virus 2), although the two antigens do not cross-react immunologically with each other (Vatti AJ et al. 2017).

In addition, T memory cells can react with B cells directly and therefore also with rare antigens, because these are "collected" by the immunoglobulin of the B cells and presented on the surface of the B cells.

Furthermore, in recent years the existence of long-lived cytotoxic T-lymphocytes could be proven, which were still detectable years after the first contact. Furthermore, it could be proven that other antigen-specific lymphocyte types such as CD4+T lymphocytes, mature B-lymphocytes and plasma cells also survive for years in the organism. These cells also represent a part of the immunological memory.

The immunological memory is successfully used in the form of vaccination or immunization. Conversely, after an allergen-specific immunotherapy, the newly established tolerance development of the immune system is also interpreted as a memory response. These memory responses are of particular clinical importance in contact allergies or autoimmune diseases.

1. Beck-García K et al (2015) Nanoclusters of the resting T cell antigen receptor (TCR) localize to non-raft domains. Biochim Biophys Acta 1853:802-809.
2. Christ A et al (2016) Long-term activation of the innate immune system in atherosclerosis. Semin Immunol 28:384-393.
3. Quintin J et al (2014) Innate immune memory: towards a better understanding of host defense mechanisms. Curr Opin Immunol 29:1-7.
4. Kondilis-Mangum HD et al. (2013) Epigenetics and the adaptive immune response. Mol Aspects Med 34:813-825.
5. Netea MG et al. (2017) Trained Immunity: An Ancient Way of Remembering. Cell Host Microbe 21:297-300.
6. Vatti AJ et al (2017) Original antigenic sin: A comprehensive review. Autoimmune 83:12-21.
7. Vukmanovic-Stejic M et al (2006) Mantoux Test as a model for a secondary immune response in humans. Immunol Lat 107:93-101.