Low mortality of children with COVID-19 may be linked to Naïve T cells

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 new study by researchers from West China Hospital, Sichuan University, Chengdu-China has found that that naïve T cells plays a very important role as to why children with COVID-19 have a lower mortality risk.

The study findings were published in the peer reviewed Journal of Evidence-Based Medicine. https://onlinelibrary.wiley.com/doi/10.1111/jebm.12454
 

During the ongoing pandemic of coronavirus disease 2019 (COVID-19), a unique phenomenon has been observed: fewer cases and lower mortality rate were observed in younger patients under the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1-3 

It is generally believed that the human immune system is in a process of continuous development from birth to adolescence and that immunity against pathogens becomes strongest in early to middle adulthood but begins to weaken in late adulthood.

Indeed, as expected, old COVID-19 patients, particularly over 70 years old, appeared higher mortality rate than the others.4-6 However, the severity of and mortality due to COVID-19 is also higher among young and middle-aged adults than among children, which does not fit the typical expectations.7, 8 

The concept that the immune system in early life (infancy and early childhood) is not yet mature suggests that the severity of and mortality due to COVID-19 should be higher among infants and children than among adults. However, according to the current data, adults, who are supposed to have stronger immunity, have a higher mortality rate than young children, as shown in the following Table 1.1-3

TABLE 1. Mortality of diagnosed COVID-19 patients in two locations

LocationDate(Age) 0∼(Age) 10∼(Age) 20∼(Age) 30∼(Age) 40∼(Age) 50∼(Age) 60∼(Age) 70∼(Age) 80∼Summary
China1, 2∼2020.11Number of diagnoses731975658013,81015,59718,19715,5977149260081,236
Diagnosis ratio0.90%1.20%8.10%17.00%19.20%22.40%19.20%8.80%3.20%100.00%
Number of deaths14255912341599410026713294
Mortality0.14%0.41%0.38%0.43%0.79%2.28%6.37%14.02%25.81%4.05%
LocationDate(Age) 0∼(Age) 5∼(Age) 18∼(Age) 30∼(Age) 40∼(Age) 50∼(Age) 65∼(Age) 75∼(Age) 85∼Summary
USA3∼2021.4Number of diagnoses510,5272,496,4385,606,9794,093,0673,716,1145,105,4971,893,720984,562573,46324,980,367
Diagnosis ratio2.04%9.99%22.45%16.39%14.88%20.44%7.58%3.94%2.30%100.00%
Number of deaths1273192260519312,71565,66095,022122,347140,129443,772
Mortality0.02%0.01%0.04%0.13%0.34%1.29%5.02%12.43%24.44%1.78%

The mortality rates vary from region to region and among time points, but the trends are similar. Why do infants and young children have much lower mortality rates than adults?

We reviewed the development of the immune system and noticed that the greatest change in the immune system with age may be in the number of naïve T cells. As shown in Figure 1A, at the time of birth, naïve T cells account for the vast majority of all peripheral T cells.9, 10 

The number of naïve T cells decreases rapidly during childhood and then declines slowly after entering adulthood. This curve is similar to the mortality curve, although the trend is just the opposite (Figure 1B).1, 3 Indeed, recent COVID-19 studies have shown that the scarcity of naïve T cells in the peripheral blood is associated with poor outcomes.11, 12 Hence, we hypothesized that the change in the number of naïve T cells might contribute to the age-related trend in mortality due to COVID-19.

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FIGURE 1 The naïve T-cell trend with increasing age is opposite to that of age-related mortality

Naïve T cells retain their specificity by expressing unique T-cell receptors (TCRs) but remain uncommitted to their helper fate until they encounter antigens presented by antigen-presenting cells (APCs). Each naïve T cell moves through the blood to the lymph nodes every 12–24 h, but only 1 in 105 naïve T cells may respond to any given antigen.

If naïve T cells do not bind to any APC-presented MHC/antigen complexes, they exit through the thoracic duct and travel back into the blood. Once a naïve T cell encounters the corresponding MHC/antigen complex, it stops circulating, becomes activated, and proliferates and differentiates into effector and memory T cells with identical antigen specificity.

Thus, the number of naïve T cells may be key to assisting the body in identifying and coping with SARS-CoV-2 infections. For everyone, both young and old, this virus is a new pathogen that has never been encountered by their immune system. Therefore, in children’s immune systems, there is essentially no difference between SARS-CoV-2 and common pediatric pathogens such as respiratory viruses, enteroviruses, and conditioned pathogenic bacteria.

The immune system needs only to recognize it, activate the adaptive immunity, and store the memory T cells, which is not different from the way in which these cells cope with other pathogens. For example, when a child first enters kindergarten, close contact with other children exposes the child to a large number of new pathogens in a short period of time, which may cause the child to be continuously infected by various bacteria or viruses. This process usually lasts for several months, and in some cases, it even lasts for one or two years. Thus, in children, SARS-CoV-2 may not be substantially different from other newly encountered pathogens.

However, after childhood, the number of naïve T cells is significantly reduced, and memory T cells become the predominant subset throughout the body. Thus, in adults, especially the elderly population, the TCR diversity of naïve T cells that have the potential to recognize new antigens has been significantly reduced (compared with in childhood).

It may happen that during many rounds of naïve T-cell patrol and circulation, a T-cell clone expressing a particular TCR that can recognize SARS-CoV-2 cannot be selected. If the immune system is unable to correctly identify a new antigen and activate the adaptive immune response, only innate immunity is activated to clear the pathogens, and the balance between viral reproduction and the innate immune response may be disrupted. If the immune system continues to fail to produce a specific adaptive immune response that can recognize SARS-CoV-2 over a long period, it is inevitable that the virus will attack all susceptible tissues and organs.

It has been reported that the proportion of naïve T cells is significantly reduced in COVID-19 patients, whereas the effector and memory subsets are proportionally increased.13 In the above description, we focused on the general number of naïve T cells before the host encounters a new pathogen. However, when the host is invaded by a pathogen that has never been encountered before, naïve T cells are converted to effector/memory T cells.

Once a T-cell clone expressing a particular TCR that can recognize SARS-CoV-2 is identified from the naïve T-cell pool, that particular clone will differentiate into effector/memory T cells, resulting in a decrease in the number of naïve T cells and an increase in the number of effector/memory T cells.

Reassuringly, SARS-CoV-2-specific T cells were found in people who had recovered from asymptomatic cases of COVID-19.14 In addition, in patients with mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed,15 and patients with severe cases experienced the loss of SARS-CoV-2-specific T cells.13 

Overall, SARS-CoV-2-specific T cells appear to retain a more activated and less exhausted profile.13, 16 These observations indicate that in severe cases, it is likely that the host fails to identify a SARS-CoV-2-specific clone from the naïve T-cell pool. However, if SARS-CoV-2-specific T cells are successfully identified and proliferate in the periphery, even when severe lymphopenia develops, the patients may still recover.

Generally, children seem to be more susceptible to infectious diseases than adults. However, this is most likely because adults have been exposed to various antigens and established immune memory of these repeatedly and chronically encountered antigens at an early age rather than the adult immune system has a better ability to recognize new antigens.

Additionally, it is unlikely that the low mortality rate in children is due to a weaker inflammatory response in children than in adults. For example, it was reported that some children develop COVID-19-related Kawasaki-like syndrome,17, 18 which is characterized by a severe inflammatory response and long-lasting fever.

It is less likely that SARS-CoV-2 induces more drastic inflammation than other pathogens but may be because in the area affected by the pandemic, the number of children potentially infected by SARS-CoV-2 is very large, increasing the likelihood of observing relatively rare cases of Kawasaki-like syndrome.

Overall, the severity of and mortality due to COVID-19 are much lower in children than in adults. The number of age-related naïve T cells was not linearly related to the mortality of COVID-19 patients, which may be due to the changes in the diversity of TCR and the viability of naïve T cells. These changes may not be directly reflected in the number of naïve T cells, but they will significantly affect the ability to recognize newly emerging antigens. Thus, the immune system in patients with severe cases may have a “pathogen identification problem” rather than an “immune overreaction problem.”

This may be a concise explanation for the observation that children with COVID-19 have mild symptoms and a low mortality rate. From this new perspective, increasing the number of naïve T cells or the diversity of TCRs may be a potential strategy to enhance the ability of the host to “search for and destroy” emerging deadly pathogens that have never been encountered by the immune system.


QUIESCENCE AND NAÏVE T CELL PARTIAL DIFFERENTIATION

Stem cell quiescence is a reversible state of growth arrest that plays an important role in tissue homeostasis and regeneration. Recent work in the area of stem cell biology has established that quiescence is not a passive process but is actively maintained by transcriptional and post-transcriptional regulation, including chromatin modification and microRNA-mediated gene repression [7,8].

Notably, there are distinct levels of stem cell quiescence, ranging from ‘deep’ to ‘shallow’ that correlated with more rapid responses and altered functional capacity in both mice and man [9,10]. A transition from deep to shallow state of quiescence is driven by signals derived from nearby or distant tissue injury, whereas the exit from quiescence occurs when there is local tissue injury. Stem cells can cycle between different states of quiescence depending on their local interactions with other cells, extracellular matrix and cytokines. During aging, stem cell quiescence is dysregulated, leading to cell death, cellular senescence and/or altered differentiation [11].

Biologically, naïve T cells are relatively similar to quiescent stem cells, particularly in their high pluripotency and proliferative potential. However, unlike stem cells, the extracellular cues for exit from quiescence are unique to naïve T cells. These cells classically retain a quiescence state until they encounter a specific antigen within their local lymph node niche. Upon direct antigen activation, naïve T cells exit quiescence, rapidly proliferate and can differentiate into numerous functional states depending on numerous factors including the local cytokine and cellular milieu.

In turn, the regulation of activation and the maintenance of cellular quiescence in T cells is extremely important for immune homeostasis, as its failure can lead to significantly perturbed immunity, such as autoimmune disease, cancer or increased infection [12]. In aging, proliferation capacity of naïve T cells appears intact however pluripotency is diminished; naïve T cells from older individuals display reduced ability to form memory and skewing of subset polarization [13,14]. These data collectively suggest a partial breakdown in cellular quiescence.

Growing evidence demonstrates that the naive T cell population epigenetically and transcriptionally shift towards a more memory-like state with age [4–6]. These memory-like features include a chromatin landscape bias towards memory cell features (e.g., increased accessibility of BATF) as well as global upregulation of differentiation-related microRNAs (e.g., mir-146a).

Possible causes of this phenotypic shift are 2-fold: (1) selection of cells with a fitness advantage or (2) adaptation of cells to an aging tissue niche. In mice, an adaptation scenario is mathematically favored, where cells adapt to their environment, acquiring survival and/or proliferative advantage with age [15]. Notably, fate mapping studies have found that the naïve T cells are epigenetically primed for different functionality based on the animals’ age when the cell was generated [16,17].

As humans lose the ability to make new naïve T cells via thymic output later in life whereas mice do not [18,19], the translatability of this age-dependent naïve T cell heterogeneity is unclear. However, recent studies using single cell analysis of human naïve T cell populations suggests that an adaptation/conversion scenario is more likely, as naïve T cells from older individuals can reacquire young-like features under certain in vitro growth conditions (unpublished data [20]).

In light of the current knowledge on stem cell biology, we propose that the shift towards a memory-like state in naïve cells with age is an adaption to an aging lymph node niche, in which naive T cells shift from a state of long-term, deep quiescence into a shallower one via age-related extracellular signals (Figure 1).

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Figure 1.
Model of Naïve T cell Quiescence with Aging.
During aging, naïve T cells (Naïve) become partially differentiated (Naïve), acquiring some features of memory T cells while retaining a phenotypically naïve state. In this memory-like naïve state, aging T cells demonstrate reduced pluripotency with altered subset differentiation post-activation. These features are similar to that observed in stem cells, where the level of quiescence (deep G0 (G0) → shallow G0 (G0)) dictates their proliferative and differentiation potentials. Thus, a model arises in which naïve T cells in young adults are maintained in a deep quiescent state whereas naïve T cells in older individuals receive altered signaling from the aging lymph node microenvironment that drives the cells towards a shallower state of quiescence. Image created with BioRender.com.

REGULATORS OF NAÏVE T CELL QUIESCENCE AND ITS BREAKDOWN WITH AGE

During aging, numerous changes occur in stem cell niches that contribute to stem cell-intrinsic dysfunction and loss of quiescence (e.g., increased inflammatory cytokines, altered extracellular matrix composition) [21]. Thus, the partially differentiated state of naïve T cells could similarly be driven by age-related changes in local lymph node niches.

In youth, naïve T cell homeostasis is maintained with secondary lymphoid tissues (SLT) (i.e., lymph nodes) by specialized stromal cells, fibroblastic reticular cells (FRCs). In animal models, aging SLTs exhibit a collapse of stromal networks, an increase in fibrosis and reductions in homing chemokines levels [22–25], suggesting FRC dysfunction during aging may be associated with naïve T cell quiescence breakdown.

FRCs classically maintain homeostasis by secretion of the essential survival cytokine IL-7. However, multiple studies on IL-7 and age have ruled out the differential production of IL-7 by FRCs as a cause of homeostatic failure in aged naïve T cells in both mice and man [25–27]. FRCs also secretes a range of other soluble factors (e.g., prostaglandin E2) that have been shown to actively suppress TCR-induced cellular differentiation [28–30].

Thus, active inhibition of differentiation signals in naïve T cells may be required to maintain a deep quiescence state and long-term survival. This idea would be similar to stem cell homeostasis where extracellular cues, such as Notch and Wnt signaling, help reenforce a quiescence state [8].

Indeed, human FRCs can directly suppresses naïve T cell proliferation and memory differentiation via the combination of factors such as TGF-beta and adenosine [31]. Adenosine and TGF-beta signaling also helps maintain naïve T cell quiescence in mice [32,33]. Whether such inhibitory factors also play a functional role in maintaining human naïve T cell quiescence and/or mediate the transition from deep into shallow quiescent states with age remains to be determined.

reference link :https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8302006/#:~:text=Na%C3%AFve%20T%20cells%20are%20critical,disease%20susceptibility%20in%20older%20individuals.

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