Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation.
Currently, the global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a greater threat to elderly people than to children and young adults, as shown by a higher frequency of severe symptoms and mortality in elderly patients, while children and young adults usually present with mild disease [1][2]. Differences in clinical severity are likely associated with immune system age [3]. Both the innate and adaptive immune systems are involved in antiviral responses. Although the innate immune system responds early, adaptive antiviral immunity is specific and robust, lasting longer in combating viral infection and generating immune memory. Adaptive antiviral immunity primarily includes neutralization antibodies (Ab) [4] associated with B cells, and cellular (mostly T cell)-mediated anti-SARS-CoV-2 immunity [5][6][7][8]. Although specific Abs are important for an immunoprotective barrier by blocking free viral particles from entering host cells, T cells and NK (nature killer, containing both innate and adaptive immune features) cells are more powerful because they destroy virally infected cells, thereby terminating viral replication. Generally, T cell priming is a key factor for effective immunity and vaccination, since T cells act not only as killer cells, but also as helper cells. For example, CD8
+
+ CTL cells [7][8], while patients with severe disease have predominantly increased SARS-CoV-2-specific CD4
+ T cells in their recovery-stage of the disease [7][8]. These differences imply that different T cell subsets have different roles in disease severity and outcome. CD4
+
+
+
+ regulatory T (Treg) cells. Th1-biased cellular immune responses typically direct the killing of the virus, while Th2-biased responses are usually associated with lung allergy in respiratory infections [9]. The roles of Treg cells reported during COVID-19 are thus far contradictory, either reportedly decreased [10][11] or relatively increased in COVID-19 patients with severe disease or/and lymphopenia [6][12][13]. The roles of Treg cells in COVID-19 patients should perhaps be assessed based on their physiological localization and disease stage. If increased Treg cells are in the lung during an inflammatory cytokine storm, this will probably be beneficial for the alleviation of the excessive immune response [14][15], but if increased Treg cells are present early in the disease, it could be detrimental to the establishment of effective antiviral immunity.
Immunosenescence and inflammaging are high risk factors for severe COVID-19 in the elderly [1][2][17][18]. As age-related thymic involution contributes to immunosenescence and inflammaging (
Table 1 third column) [16], thymic function should also be considered as a potential player in aged populations versus young [19][20], and may also impact vaccination efficiency in the elderly. One indication that thymic function participates in COVID-19 disease severity has been reported, in which thymosin alpha-1 (T α 1, a synthetic thymic peptide) reduced the mortality of patients with severe COVID-19 [21], and a clinical trial with T α 1 to treat COVID-19 infection in elderly patients was approved (
https://clinicaltrials.gov/ct2/show/NCT04428008
Figure 1.
A
B
Table 1.
Normal Thymus Maintains Homeostasis and Immunity | Age-related Thymic Changes Contribute to Viral Infection | Potential Rejuvenation Strategies | ||||
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Thymus | 1. Sufficient naïve T cell generation with highly diverse TCR repertoire 2. Minimal self-reactive T cell generation 3. tTreg generation balanced with tTcon generation |
1. Reduced functional naïve T cells 2. Increased self-reactive T cells 3. Enhanced tTreg generation in proportion to tTcon output |
Thymic rejuvenation via: 1. Injecting reprogrammed | FoxN1 | over-expressing fibroblasts 2. Providing exogenous factors such as growth hormone, IL-7, etc. |
|
Peripheral lymphoid tissues and circulating blood | 1. T cells with normal TCR repertoire → a broad recognition of foreign antigens 2. Potent T cell immune response to foreign antigens and homeostatic clearance of senescent somatic cells 3. pTreg cells balanced with pTcon cells → maintenance of immune tolerance and antiviral immunity. |
1. Immunosenescence: | Restricted TCR repertoire diversity → compromised viral antigen recognition Accumulated exhausted T cells → compromised anti-viral immune response and senescent somatic cell clearance → inflammaging Accumulated pTreg → suppress normal antiviral immune responses | 2. Inflammaging: | Self-reactive T cell induced tissue damage → chronic basal inflammation → inhibition of T and B cell activation for antiviral responses |
1. Enhance peripheral T cell function via: a. TGF-β blockade to inhibit iTreg cells b. PD-1 blockade 2. Reduce chronic inflammatory conditions via low-dose mTOR inhibitors, aspirin, etc. |
Lung | 1. Sufficient cellular and humoral antiviral immunity 2. Timely clearance of virus by appropriate pro-inflammatory responses |
1. Reduced antiviral function by T cells and plasma cells 2. Inflammatory cytokine storm facilitated by inflammaging 3. Lung tissue fibrosis after inflammation |
TGF-β blockade to reduce fibrosis |
Based on currently available evidence from the current COVID-19 pandemic, most cases present with mild respiratory distress symptoms, with only a few of cases having severe pneumonia [22]. Among the severe cases, the majority are adults with underlying health conditions and elderly individuals. Children and young adults exhibit less susceptibility to the disease than the elderly [19][23][24]. Although it is proposed that one reason for the reduced clinical severity in children is due to reduced expression of angiotensin-converting enzyme 2 (ACE-2) receptors, which is the key receptor needed for SARS-CoV-2 infection of epithelial cells of the host respiratory tract [25], the overall robustness of the immune system is also a key distinction between young and old individuals. Studying the unique characteristics of the immune system in children and young adults, including innate and adaptive components, will likely reveal the potential mechanisms needed to understand efficient antiviral immunity and vaccination in the elderly.
Changes in the aged immune system [26][27][28] result in anti-infection immune insufficiency (immunosenescence) and self/auto-immune enhancement (partially contributing to age-related chronic inflammation, i.e., inflammaging). One of the most obvious age-associated alterations in the aged immune system is the involution/atrophy of the thymus [16][29]. The thymus plays a key role in cellular immune function and it continuously develops undifferentiated thymocytes into functional naïve T cells throughout the lifetime to facilitate adaptive immunity. However, the thymus undergoes progressive physiological involution with age [30]. The involuted thymus exhibits reduced naïve T cell output, contributing to a restricted TCR repertoire with reduced ability to recognize neo-antigens, which results in increased susceptibility to infection. Meanwhile, the involuted thymus exhibits increased self-reactive T cell output due to defective negative selection, which results in increased self-reactivity associated with autoimmune proneness and inflammaging [16]. Additionally, as various types of coronaviruses are able to induce thymic involution, SARS-CoV-2 could also possibly damage thymus [20], which further deteriorate the functionality of aged thymus in T cell generation. Thus, we can assume that the decline in T cell immunity via thymic involution is potentially involved in the increased morbidity and mortality of COVID-19 in the elderly.
It is unclear how T cells are involved in SARS-CoV-2 infection [31]. However, lower peripheral blood T cell counts (lymphopenia) are observed in severe COVID-19 patients [6][13], with further reductions in those admitted to intensive care units (ICUs) and in those over the age of 60 [32], whereas increased SARS-CoV-2-specific T cells are associated with disease recovery [33][34][35][36]. There are three potential reasons for lymphopenia in severe COVID-19 patients. One is likely due to the SARS-CoV-2 spike proteins directly interacting with CD26 on T cells, leading to T cell apoptosis and immune dysfunction [37][38]. The second is due to the relocation of T cells, assuming that a large number of T cells in the blood are recruited to the lung [15][39]. Additionally, the third, seen in aged patients, is possibly attributed to the aged patient’s low thymopoiesis [40][41], which in conjunction with immunosenescence, reduces efficient peripheral T cell activation and differentiation for the necessary anti-infection response [42].
The exact roles of the aged T cell system in the clinical severity of COVID-19 disease remains unclear, but there are at least three considerations, which can all be traced back to the aged, atrophied thymus, and the consequences of immunosenescence and inflammation. First, immunosenescence (reduced immune responsiveness) in the T cell system is attributed to both decreased output of functional naïve T cells and accumulated exhausted/senescent memory T cells in the periphery, and restricts overall TCR diversity [43][44]. Second, immunosuppression from enhanced and accumulated polyclonal Treg cells, which serve the vital function of suppressing excess immune responses mediated by effector T (Teff) cells and other immune cells both with and without antigen-specificity (polyclonal Treg cells can exert bystander suppressive effects), serves to maintain immunological self-tolerance. In aged individuals, however, abnormally accumulated peripheral regulatory T (pTreg) cells may negatively impact anti-infection responses and vaccination. Third, inflammaging, which is partially attributed to increased self-reactive T cell output, could exacerbate COVID-19 pathology and possibly inhibit T cell responses to vaccination [3].
In addition, many uninfected healthy people were reported to have pre-existing SARS-CoV-2-specific T cells, possibly due to the cross-reactive memory T cells induced by previous infection with coronaviruses of the common cold, and these individuals seem less susceptible to SARS-CoV-2 infection [33][34][35][36]. This confirms the critical function of T cells in anti-SARS-CoV-2 immunity. The pre-existing common cold-specific memory T cells in the elderly could be exhausted and/or senescent, which is another reason that the aged people cannot adapt to new infection. Thus, it is reasonable to speculate that for these reasons, aged people are highly susceptible to severe SARS-CoV-2 cases with a poor prognosis, and may experience lower efficacy with COVID-19 vaccines, compared to young adults.
Age-related thymic involution alters T cell profiles in ways that compromise immune function exhibited by several obvious characteristics, the first of which is reduced output of functional naïve T cells [30][45][46][47], which, coupled with accumulated exhausted/senescent memory T cells, results in a restricted TCR repertoire diversity, and contributes to immunosenescence, i.e., cellular immune functional insufficiency [48]. The second is increased output of self-reactive T cells, resulting in increased self-reactivity [49], involved in inflammaging, i.e., enhanced basal inflammation in the elderly [50][51][52]. Although seemingly opposing functions, these two phenotypes are interconnected [16][53]. The third is relatively enhanced polyclonal thymic regulatory T cell (tTreg) generation via an increased ratio of newly generated tTreg cells to thymic T conventional (tTcon) cells [54], which potentially exacerbates the age-related accumulation of pTreg cells [55][56][57][58]. The outcome of excess pTreg cells in the elderly is likely a disruption of immune homeostasis or imbalanced responses against foreign antigen and/or suppression of self-antigen-directed responses. Herein, we suggest that the impacts of these alterations in the aged T cell system, associated with age-related thymic involution, are potentially involved in the clinical severity of COVID-19 infection in elderly patients.
neg- T cells, which cannot receive the necessary secondary T cell activation signaling [59][60][61], and exhibit multiple senescent markers, such as programmed cell death protein 1 (PD-1) [62][63] and p16(INK4a) [64][65][66]. Therefore, these senescent T cells (CD28
-neg
+
SP
SP
+
Increased output of self-reactive T cells from the aged, atrophied thymus results from perturbation of thymocyte negative selection [49][67]. These self-reactive T cells potentially participate in inflammaging, by infiltrating into non-lymphoid tissues and inducing self-tissue damage. This is concomitant with the previously defined chronic activation of innate immune cells in the elderly, which in conjunction with somatic cellular senescence produced SASP, results in increased circulating pro-inflammatory cytokines, characterized by above baseline serum concentrations of C-reactive protein (CRP), TNF-α, IL-6, and IL-8, in the elderly [68][69][70]. Inflammaging could exacerbate COVID-19 pathology and might even inhibit T cell responses to SARS-CoV-2 vaccines [3], due to downregulating the expression of T cell co-stimulatory molecule CD28 [71][72]. This pre-existing inflammatory condition may also initiate an inflammatory cascade that results in hyper-inflammatory responses in the lung during SARS-CoV-2 infections in older patients [3]. We speculate that the increased basal levels of pro-inflammatory signals and sub-clinical self-tissue damage might predispose certain individuals to certain types of infections that merely exacerbate the underlying immuno-reactive microenvironment in those tissues, such as the lung in the case of COVID-19. Indeed, our investigations have shown that in mice with thymic involution, there was increased lymphocyte infiltration into self-tissues, including the lung [67]. Although there is increasing interest in the correlation between immunosenescence and the increased risk of COVID-19 mortality in the elderly, more research is needed to fully elucidate the role of pre-existing lung inflammation and infiltration of potentially self-reactive T cells during COVID-19 pathogenesis [73][74][75][76].
Treg cells play a vital function in suppressing excessive immune responses mediated by Teff cells and other immune cells (B, DCs, NK, etc.), both with and without antigen-specificity, in order to maintain immunological self-tolerance [77][78]. However, it is also well established that pTreg cells accumulate with age and this abnormal accumulation has been implicated in immunosuppression of anti-infection and anti-tumor immunity, and inhibition of vaccination efficacy in the elderly [56][57][79]. For example, (a) in chronic
Leishmania major
Studies on Treg cells in COVID-19 patients are insufficient, but some reports showed that Treg cells within peripheral blood mononuclear cells (PBMCs) of COVID-19 patients were decreased [10][11], while other reports found a relative increase in COVID-19 patients with severe disease or/and lymphopenia [12][13]. If the decreased Treg cells in PBMCs are due to the pulmonary recruitment of these cells along with Teff cells [15], which is one of the potential reasons for lymphopenia in severe COVID-19 patients [6], perhaps we should ask why aged patients do not have less lung inflammation compared to young COVID-19 patients, since those aged Treg cells have relatively enhanced suppression function [79].
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