Development and Localization of the Immune System during Life with a Focus on the Respiratory Tract

How the immune system develops during lifetime and the protection at frequent pathogen entry locations is strengthened. In jargon, the ontogenesis and the generated compartmentalization of the immune system.

Entire page is in work, incomplete and some parts need checking. Early online to contribute to a rational discussion which measures (pharmaceutical and non-pharmaceutical) are adequate and/or needed for the different age groups with a focus on the young.

A main reason for the early publishing is the literature list which inspires and founds this chapter.

References to figures refer to the figures in the corresponding papers.

Conceptual Summary
Relevance regarding SARS-CoV-2 Infections
Selected Literature on the Immune System throughout Life
Observations grouped by Mechanism
Development Stages at different Ages
References

Conceptual Summary

The human immune system changes throughout the lifetime and these changes are closely interlinked with ageing from birth to death. The microbes encountered at the different entry locations shape and train the immune system both locally and body wide. At some point all microbes are new and mostly encountered at young age. Thus at young age the immune system is primed to handle new microorganisms. With increasing age the immune system relies more and more on the skills learned from previous exposures.

Infants recognize and handle new microorganisms well, thanks to strong innate recognition mechanisms and a permanent alertness of the immune system. The recognition and the handling relies on 1) innate mechanisms, 2) inherited information of the acquired immunity and 3) the immune system support through substances, antibodies and immune cells from the mother e.g. through the mother milk. Additionally the entry locations need to be tuned. E.g. unknown viruses entering the lungs is fairly new from an evolutionary perspective. Furthermore the body is in early development and so the cell-lineages themselves and their cooperations mechanisms are just being built up. For these reasons, unspecific innate responses are key at this stage. It is not uncommon that infants need to initiate high fever to control virus infections - which has temporarily high fitness costs - but reduces many virus infections efficiently.
After a few years of life the immune system is strong since it has encountered many pathogens and learned: Surveillance and protection at frequent pathogen entry locations and a repertoire of mechanism to adequately handle different pathogens. The learning of new pathogens works very well at this stage.
In early adulthood the ability the learn completely new pathogens decreases since the innate recognition mechanism are relaxed. The homeostasis is focussed on functionality. However the recognition and learning of microorganisms similar to existing ones is strong due to the gained experiences at which locations which microorganisms enter and the gained experiences how to handle the different classes of microorganisms.
With increasing age the immune system relies more and more on a large immune memory built up throughout life. Nevertheless learning to handle new microorganisms - especially if the microorganisms have similarities to encountered ones - is still possible although slower.
At old to very old age, cells including immune cells are subject to senescence. The cells and the body do not work as perfectly anymore:
- Often something is detected out of order - even without microorganisms interfering - which can cause inflammation. To prevent autoimmunity the inflammation needs to be controlled and therefore the immune system alarming is more relaxed.
- The functionality is reduced. E.g. cells taking up and carrying antigens to antibody producing cells migrate slower (dendritic cells take up pathogen part and bring them to the lymph nodes where an interplay between CD4 T cells and B cells induces antibody production). Cells can reach end of life (mostly by apoptosis) whereby some acquired memory is lost.
Overall the immune system is less performant at this stage.

Relevance regarding SARS-CoV-2 Infections

At young age the immune system is built to encounter new pathogens and handle them appropriately: It is well known that if one encounters a completely new pathogen for the first time as adult, the disease is usually more severe. The handling of ‘somewhat new’ pathogens works also well for young adults due to cross immune mechanisms both recognition and effector functions. SARS-CoV-2 is a ‘somewhat new’ virus: SARS-CoV-2 as a new coronavirus, is new to the immune system in some aspects (e.g. regarding virion binding antibodies), but not in other aspects (such as some T cells epitopes) since it shares conserved units with the endemic human coronaviruses (mainly with the betacoronaviruses OC43 und HKU1). The immune system knows to handle the endemic coronaviruses.

For infants and children SARS-CoV-2 is just another new virus e.g. like the other endemic human coronaviruses. For coronavirus unexposed people, the current SARS-CoV-2 strains are even less pathogenic than the endemic human coronaviruses since the latter have evolved to evade the human (innate) immune system.

SARS-CoV-2 lineages are becoming better at evading innate immune mechanisms but only slowly. I except it will take many years until SARS-CoV-2 comes close to the capabilities of the endemic coronaviruses at avoiding the innate immune system. One reason for the slow adaption is, that many units of coronaviruses are multifunctional, so improving one function often diminishes another function.
For adolescents and young adults SARS-CoV-2 is not dangerous neither: Both innate and acquired (mainly coronavirus-cross-reactive tissue resident T cells) immune mechanisms recognize the infection. The pool of immune cells to recruit is still large enough (and even shaped to recognize coronaviruses) to give rise to an adequate and virus controlling immune response. Nearly always the immune response is timely enough to prevent the viruses spreading throughout the lungs and thus severe disease is prevented.
With increasing age the recognition of new viruses and the capabilities to handle them decreases. One of the reason is the low count of naive T cells with are crucial to produce a highly specific immune response; accordingly Moderbacher et al observe that low counts of naive T cells are well correlated both to severe Covid and age. Additionally the body works slower which delays a timely immune response.

Selected Literature on the Immune System throughout Life

Lloyd and Marsland - in a readable review - describe several aspects how the lung immune system developes and highlight the importance of the exposure to microbes.
Kumar, Conners and Farber review how:
- How the immune system is developes at the different locations throughout life (e.g. Figure 3) and is associated with pathogens encountered at the different sites. A focus is the compartmentalization and tissue residency, a topic in which the research group from Mrs. Farber does pioneering work.
- Differences between the immune system development in mice and human are pointed out: E.g. in human the generation of naive T occurs often locally in tissues where as in mice it occurs mainly in the thymus. Also the lifespan of naive T cells is much longer in humans with a lifespan of 5 to 10 years compared to a few weeks in mice.
Zheng et al investigate the systemic immune cell landscape in young and old adults: Peripheral blood mononuclear cells are analyzed by single cell single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq). Additionally mass cytometry is carried out in a cohort of Covid infectees and RNA sequencing in a cohort of recovered Covid patients (Fig. 1 B).
Moderbacher et al investigate the systemic CD4+ and CD8+ T cell and neutralizing antibody responses of Covid patients. Correlations between the percentage of naive CD4 and CD8 cells and the severity of Covid is found (Figure 6 E for CD4 and F for CD8).
Loske et al investigate the cells in the upper respiratory tract at steady state and during SARS-2 infections of persons of different ages by single-cell RNA sequencing. They find that the upper airways of children are primed to sense and handle infections both by an increased prevalence of immune cells and the expression profile of epithelial cells.

Observations grouped by Mechanism

Surveillance for New Pathogens and Dangers

Innate immune recognition works best at young age:

Loske et al find that the genes of the pathogen recognition receptors MDA5 (IFIH1) and RIG-I (DDX58) are expressed at higher levels and at higher percentages of cells across many upper respiratory tract cells in younger people (Fig. 2 b). The usefulness in preventing an infection of these receptors is demonstrated that people with higher expression rates of these PRR have less symptoms (Fig. 2 c).
At high age, endoplasmic reticulum stress is common in many cells in order to keep full filling their tasks the associated danger signals are down regulated, which reduces the chance to detect viruses by ER stress, which is especially relevant for positive stranded RNA viruses as coronaviruses [to confirm and cite].

Alertness of the Immune System

At young age the homeostasis is more focussed on infection prevention whereas with increasing age to homeostasis shifts towards functionality and house keeping (including waste removal):

Zheng et al observe that the proportion of T cells in blood mononuclear cells is higher for young people than for older (55% versus 40%) whereas the proportion of macrophages increases with age (13% to 22%) // Remark: macrophages can handle viruses to some extent (best with support from acquired immunity). T cells on the other hand are specialized to handle virus infections.
Loske et al show in Fig 1: In the upper respiratory tract of uninfected adults, few immune cells are present and most cells present are ciliated or structural cells. In children on the other hand even when not infected the cell landscape resembles that during infection with a large number of different immune cells present: Neutrophils, different types of T cells and B cells.

Immune Response Time

Initiating an immune response is faster in young age:

Zhao et al observe that dendritic cells migrate slower to the lymph nodes in young old mice compared to young mice.
Loske et al find that at young age the cellular communication, measured by ligand receptor interactions, is increased (Fig. 3 a).

Reliance on Acquired Immunity

With increasing age the immune system relies more and more on the acquired immunity built up throughout lifetime. The capabilities to build up new acquired immunity decrease especially regarding completely new targets:

Throughout life the distribution of T cells shifts from naive T cells shift to effector T cells ( Kumar et al: Figure 3, Zheng et al: Figure 2 B by RNA seq and 2 C by mass cytometry, Moderbacher et al: Figure 6 D for percentage of naive CD4 and 6 F for percentage of naive CD8). The shift is strongest at the mucosal sites such as the intestine and the lungs (Figure 3 in Kumar).
The T cell and B cell receptor diversity is highest at young age. With increasing age the diversity decreases while the receptors have higher degrees of rearrangements (Zheng et al: Text and Figure 5) and are selected by previous pathogen exposure [to confirm and city]. It is to except that the immune response is de novo optimized for SARS-2 in young people, while in older it is strongly influenced by the endemic human coronaviruses (Selva et al note this because they observe that older people are more likely have antibodies targeting the S2 domain of S or the nucleocapsid protein which have a higher conservations rate across coronaviruses. To target epitopes in conserved parts - such as S2 and parts of N - has the advantage that these epitopes are less likely to mutate and when they mutate fitness costs are likely).
With increased age the genes responsible for the adaptive immune responses are up regulated in blood mononuclear immune cells (T-, NK- and B-Cells, Macrophages, Dendritic cells) as shown in Zheng figure 3 B.

Cellular Performance during Life

With increasing age the immune cells become senescent which reduces and alters several functionalities:

Zheng et al observe various changes by looking at differentially expressed transcription factors.
As noted in immune response time dendritic cells in mice migrate slower at increased age (Zhao et al).

Development Stages at different Ages

work in raw form and incomplete

Immune System as Fetus

in work

Kollmanm et al, remarks that the immune system niches are populated as fetus. Also noted in Kumar et al [to check].

Immune System as Infant

Learning of the Immune System

Learn where pathogens and danger enter the body and strengthen the surveillance and protection at these locations [to cite].
Learn how to learn: The training of the acquired immune system is innate but it can be optimized [to confirm and cite].

Protections Provided

Good innate defenses but only partly optimized to entry locations and viruses for evolutionary reasons. However this is improving by each generation since the immune system is good a passing on information to the next generations.
- The lungs are a weak point since until a few generations ago the probability to encounter directly in the lungs was low. Thus lung immunity is often lifetime trained and only partly innate.
- There has been not much evolutionary pressure to adapt to new intracellular pathogens such as new viruses right after birth: Unlike extracellular pathogens, intracellular pathogens tend to be species specific and thus are associated to dense population settings.
Few acquired immunity. Naive T cell are present throughout the body but few memory cells have are established [to check (theoretically memory cell could be established as foetus since in humans but not in mice T cells are already present) and cite].
Through the mother milk antibodies and other immune substances support the protection.

Immune System in Childhood

Learning of the Immune System

Strengthen the immunity for frequent entry locations and pathogen patterns.
Train the acquired part of the immune system. Build up a collection of memory T cell and B cell recognizing specific pathogens i.e. build up a library of specific pathogen recognizers.

References

References Immunity Upper Respiratory Tract

Loske

Loske, J., Röhmel, J., Lukassen, S. et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat Biotechnol (2021). https://doi.org/10.1038/s41587-021-01037-9

References Ontogenesis of the Lung Immunity

Lloyd

Lloyd, C. M., & Marsland, B. J. (2017). Lung Homeostasis: Influence of Age, Microbes, and the Immune System. Immunity, 46(4), 549–561. https://doi.org/10.1016/j.immuni.2017.04.005

References Immunity Infants and Children

Lambert

Lambert L and Culley FJ (2017) Innate Immunity to Respiratory Infection in Early Life. Front. Immunol. 8:1570. https://doi.org/10.3389/fimmu.2017.01570

Kollmann

Kollmann, T. R., Kampmann, B., Mazmanian, S. K., Marchant, A., & Levy, O. (2017). Protecting the Newborn and Young Infant from Infectious Diseases: Lessons from Immune Ontogeny. Immunity, 46(3), 350–363. https://doi.org/10.1016/j.immuni.2017.03.009

References Immunity regarding CoVs Infections throughout Life

Selva

Selva, K.J., van de Sandt, C.E., Lemke, M.M. et al. Systems serology detects functionally distinct coronavirus antibody features in children and elderly. Nat Commun 12, 2037 (2021). https://doi.org/10.1038/s41467-021-22236-7

Moderbacher

Rydyznski Moderbacher et al., Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity, Cell (2020), https://doi.org/10.1016/j.cell.2020.09.038

this article by Moderbacher et al inspired the discussion of naive immune cells in this chapter.

Cohen

Cohen, C.A., Li, A.P.Y., Hachim, A. et al. SARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection. Nat Commun 12, 4678 (2021). https://doi.org/10.1038/s41467-021-24938-4

References Human Immunity throughout Life in Humans

Kumar

Kumar, B. V., Connors, T. J., & Farber, D. L. (2018). Human T Cell Development, Localization, and Function throughout Life. Immunity, 48(2), 202–213. https://doi.org/10.1016/j.immuni.2018.01.007

Zheng

Zheng, Y., Liu, X., Le, W., Xie, L., Li, H., Wen, W., Wang, S., Ma, S., Huang, Z., Ye, J., Shi, W., Ye, Y., Liu, Z., Song, M., Zhang, W., Han, J. J., Belmonte, J., Xiao, C., Qu, J., Wang, H., … Su, W. (2020). A human circulating immune cell landscape in aging and COVID-19. Protein & cell, 11(10), 740–770. https://doi.org/10.1007/s13238-020-00762-2

Zhou

Zhou D, Borsa M, Simon AK. Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells. Aging Cell. 2021;20:e13316. https://doi.org/10.1111/acel.13316

References Immunity throughout Life in Animals

Summary Zhao

Zhao, J., Zhao, J., Legge, K., & Perlman, S. (2011). Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. The Journal of clinical investigation, 121(12), 4921–4930. https://doi.org/10.1172/JCI59777

Results

in work

T cell recruitment works less well in old mice compared to young mice (after MA15 infection). One reason is that the that the dendritic cell migration from the respiratory tract to the draining lymph nodes is impaired (due to increased PGD2 levels). This in turn reduces the recruitment of (MA15-specific) T cells.

Wong

Wong, C. K., Smith, C. A., Sakamoto, K., Kaminski, N., Koff, J. L., & Goldstein, D. R. (2017). Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice. Journal of immunology (Baltimore, Md. : 1950), 199(3), 1060–1068. https://doi.org/10.4049/jimmunol.1700397

Tallmadge

Tallmadge RL, Wang M, Sun Q, Felippe MJB (2018) Transcriptome analysis of immune genes in peripheral blood mononuclear cells of young foals and adult horses. PLoS ONE 13(9): e0202646. https://doi.org/10.1371/journal.pone.0202646

References Immune Cell Niches and Renewal

McQuattie-Pimentel

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

recommended to read van de Laar first

Results

[in work and to check] All experiments/results for mice. There’s a niche of tissue resident macrophages in the thoradic which persists throughout lifetime (Figure 1 A and B). Upon injury of this niche (sublethal influenza or intratracheal bleomycin), monocyte-derived alveolar macrophages are recruited and induce a permanent population in the niche (Figure 1 G and H). The alveolar macrophage RNA-Seq expression profile is mostly determined by the (micro) environment and is not cell-lineage intrinsic (Figure 2).

van de Laar

van de Laar et al., 2016, Immunity 44, 755–768 April 19, 2016 a2016 Elsevier Inc. http://dx.doi.org/10.1016/j.immuni.2016.02.017