Trained immunity: is there an innate immunological memory?

By Iulia Kis

For the longest time, the immune system has been divided into its innate and adaptive arms. One of the major distinguishing factors between the two is that the adaptive immune system very clearly develops immunological memory. This means that upon re-challenge with the same pathogen, the host’s immune response will be much quicker and more effective. Lately, this divide has been challenged by the introduction of trained immunity. Adaptive immunity, and implicitly immunological memory, is common between jawed vertebrates, but plants, invertebrates and jawless vertebrates lack it. Consequently, the immune response and necessary time to clear an infection in these organisms should be very similar between the first and second exposure to the same pathogen. 

This assumption was challenged multiple times in the past, notably by a 2006 study (Sadd & Schmid-Hempel, 2006) in which bumblebees were infected with a gram-negative bacterium that was easily clearable (Pseudomonas fluorescens) and two very similar gram-positive bacteria (Paenibacillus alvei and P. larvae).  It was shown that the bumblebees previously injected with bacteria had much higher survival rates then the control. These were highest and most consistent as time passed when they had previously received a homologous injection. For heterologous injection, protection was enhanced very much when the second exposure was at 8 days from the first, but this was not as noticeable after 22 days. This was a controversial finding at the time, implying that the innate immune system retained some memory characteristics, even if short-lasting.

 Studies in mice showed very early on that administration of β-glucan, present in the cell walls of bacteria and fungi, provided the animals with enhanced immune responses against Staphylococcus aureus (Di Luzio & Williams, 1978). Similar effects were observed when mice treated with the peptidoglycan muramyl dipeptide 1 day before infection with Toxoplasma gondii were resistant to it. (Krahenbuhl et al., 1981) However, treatment up to two weeks before infection did not have a significant effect, which, at the time, suggested the “innate immune memory” was very short lived.

These features were later attributed to macrophages, which enhanced their expression of pattern recognition receptors (PRRs) upon re-challenge. (Bowdish et al., 2007) One such PRR is Dectin-1, which contains an immunoreceptor tyrosine based activation motif that aids its immunomodulatory functions. Its main function is recognizing yeast infections through binding of beta glucans and eliciting production of pro-inflammatory cytokines. In Dectin-1 knock-out mice, infection with Candida albicans or Saccharomyces cerevisiae results in a much lower macrophage activation and an impaired immune response. The mice had no abnormalities in their response to other types of pathogens, showing the importance of this receptor in clearing fungal infection. (Taylor et al., 2007) 

In humans, the BCG vaccine induces non-specific immunity, with studies showing that administration of this vaccine at birth reduces neo-natal deaths that are not related to accidents or tuberculosis by as much as 25%. The reason for this is that it provides cross-resistance to diseases like malaria and yellow fever by augmenting the pro-inflammatory effects of monocytes. (Netea et al., 2020) The same vaccine is used to treat bladder cancer, leukaemia, melanoma and lymphoma, mainly due to its effects on autophagy, which induces trained immunity in monocytes and macrophages. (Buffen et al., 2014) 

The term “trained immunity” was first proposed in 2011 and was defined as the heightening of the immune response upon reinfection with the same or a similar pathogen (cross-protection). This was attributed to two mechanisms. The first was the quantitative increase of innate immune system components such as PRRs, receptors for pathogen structural molecules like peptidoglycans and an increase in phagocytic capabilities. The second was somatic diversification, which is similar to lymphocyte specificity formation, but does not include rearrangement. (Netea, Quintin & Van Der Meer, 2011) This was observed in jawless vertebrates, which lack the adaptive arm of the immune system, but their lymphocytes possess leucine-rich receptors which can be inserted in variable lymphocyte receptor germline genes and provide adaptable cells with some immunological memory. (Pamcer et al., 2004) 

Since the first theories, it has been shown that the major mechanism that plays a role in trained immunity is epigenetic reprogramming resulting in a more rapid and different transcriptional response upon re-challenge with the same pathogen.  The stimulation of innate immune cells can leave mark on the affected genes, making them more responsive long-term. (Netea et al., 2020) Immune priming long non-coding RNAs (IPLs) have been found to enable histone modification of genes coding for cytokines. Even more compelling evidence for the importance of IPLs in training genes is that mice that lack the prototypical IPL UMILIO had it inserted, resulting in the training of immune genes. (Fanucchi et al., 2019)

Despite the benefits listed above, trained immunity also has downsides, like its role in chronic inflammatory diseases. For example, in atherosclerosis, monocyte recruitment at the affected site is a major influence in diseases development. If this step is slowed down by impeding the reception of chemokines, atherogenesis is retarded (Boring et al., 1998). Trained immunity enhances the pro-inflammatory cytokine production by monocytes, so the hypothesis that microorganism infections could be correlated with increased risk of cardiovascular disease is entirely valid. (Tercan et al., 2020)

In the end, it is clear that the concept of trained immunity has blurred the boundary between the features of the adaptive and innate immune systems. Work still needs to be done in this field to uncover the inner mechanisms of trained immunity and how it can be used as a potential target for cancer therapies. At the moment, current research on clinical applications proposes to use the trained immunity obtained from the BCG vaccine against SARS-CoV-2 or to block it altogether to prevent inflammatory diseases. These are promising perspectives that really deem this topic worthy of attention in the field of immunology.

References:

Sadd, B.M. & Schmid-Hempel, P. (2006) Insect Immunity Shows Specificity in Protection upon Secondary Pathogen Exposure. Current Biology. [Online] 16 (12), 1206–1210.

Di Luzio, N.R. & Williams, D.L. (1978) Protective effect of glucan against systemic Staphylococcus aureus septicemia in normal and leukemic mice. Infection and Immunity. [Online] 20 (3), 804–810.

Krahenbuhl, J.L., Sharma, S.D., Ferraresi, R.W. & Remington, J.S. (1981) Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice. Infection and Immunity. 31 (2).

Bowdish, D.M.E., Loffredo, M.S., Mukhopadhyay, S., Mantovani, A., et al. (2007) Macrophage receptors implicated in the ‘adaptive’ form of innate immunity. Microbes and Infection. [Online] 9 (14–15), 1680–1687.

Taylor, P.R., Tsoni, S.V., Willment, J.A., Dennehy, K.M., et al. (2007) Dectin-1 is required for β-glucan recognition and control of fungal infection. Nature Immunology. [Online] 8 (1), 31–38.

Netea, M.G., Domínguez-Andrés, J., Barreiro, L.B., Chavakis, T., et al. (2020) Defining trained immunity and its role in health and disease. Nature Reviews Immunology. [Online]. 20 (6) pp.375–388.

Buffen, K., Oosting, M., Quintin, J., Ng, A., et al. (2014) Autophagy Controls BCG-Induced Trained Immunity and the Response to Intravesical BCG Therapy for Bladder Cancer. PLoS Pathogens. [Online] 10 (10), 1004485.

Netea, M.G., Quintin, J. & Van Der Meer, J.W.M. (2011) Trained immunity: A memory for innate host defense. Cell Host and Microbe. [Online]. 9 (5) pp.355–361.

Pamcer, Z., Amemiya, C.T., Ehrhardt, G.R.A., Coitlin, J., et al. (2004) Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature. [Online] 430 (6996), 174–180.

Fanucchi, S., Fok, E.T., Dalla, E., Shibayama, Y., et al. (2019) Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nature Genetics. [Online] 51 (1), 138–150.

Boring, L., Gosling, J., Cleary, M. & Charo, I.F. (1998) Decreased lesion formation in CCR2(-/-) mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. [Online] 394 (6696), 894–897.

Tercan, H., Riksen, N.P., Joosten, L.A.B., Netea, M.G., et al. (2020) Trained Immunity: Long-Term Adaptation in Innate Immune Responses. Arteriosclerosis, Thrombosis, and Vascular Biology. [Online]. 41 (1) pp.55–61.