Nature Immunity: Ten Characteristics of T Cell Aging

When people get old, not all of them will get sick, but aging will give disease opportunities. The immune system is the firewall for the body to respond to various internal and external crises ( it can defend against enemies externally and maintain stability internally ). As the body gradually ages, the immune system is gradually eroded by the years. As a result, the body's ability to respond to pathogens and cancer cells gradually weakens. T cells are an important part of the immune system and play a central role in cellular immune responses. If T cells are senescent, what changes occur during aging? In June 2021,  a landmark review article Hallmarks of T cell aging was published in the international academic journal Nature Immunology  , which introduced ten characteristics of T cell aging. Today, we try to decipher it.

Immune senescence and T cell senescence

Aging adaptive immunity is characterized by progressive dysfunction and enhanced autoimmunity, leading to increased infection, increased susceptibility to cancer, and reduced vaccine efficacy. Studies have shown that changes in CD4+ T cells can induce chronic inflammation and aggravate aging phenotypes throughout the body, supporting the view that T cell aging plays a major role in the body's systemic aging .

T cell senescence may be one of the main features of "immunosenescence" . Aging of the immune system interferes with its firewall function (elimination of foreign pathogens or mutated cells in the body) , while inducing inflammation and autoimmune disease. T cell progeria can be "contagious," that is, accelerate the aging of multiple organs and systems. Immunodeficiency resulting from knockout of perforinaccelerated accumulation of senescent cells and thus the aging process, suggesting that a failure of immune surveillance may lead to systemic aging.

Four main features

Thymus degeneration

The most well-documented change in the aging of the immune system is the degeneration of the thymus gland, the main organ responsible for the production of T cells. The degeneration of the human thymus begins in childhood and peaks in adolescence . Age-related thymic degeneration manifests as destruction of tissue architecture, loss of thymus mass, and decline in thymocyte numbers. This leads to the reduction of naive T cells arriving in the peripheral blood, the compensatory clonal expansion of memory T cells, and the reduction of the diversity of the peripheral T cell pool, which affects the detection of pathogens.

Increased levels of sex steroids and decreased production of growth factors such as growth hormone, IGF-1, and KGF promote thymic regression. Thus, reduction of sex steroids by surgical or chemical castration can induce restoration of thymic function . Conversely, stress, infection, obesity, pregnancy, and antineoplastic treatments accelerate thymic regression.

The inability of older adults to restore immune function after injury from chemotherapy, ionizing radiation, and infection increases disease morbidity and mortality. Therefore, it is crucial to develop strategies to enhance thymus function and promote immune reconstitution.

Stress-mediated thymus atrophy was prevented by additional administration of growth hormone/leptin/ ghrelin etc. Injection of ghrelin significantly enlarged the thymus, cell number and T cell output in aged mice. Ghrelin infusion can significantly increase thymus size, cell number and T cell output in aged mice. In addition, IL-22 may also promote thymus regeneration in mice. Notably, people who exercised regularly had increased frequencies of naive T cells and newly emigrated thymocytes, as well as elevated circulating levels of IL-7 . In addition to hormones and growth factors, thymus transplantation and adoptive cell therapy may also stimulate thymus development in mice.

Notably, the mechanisms underlying thymic atrophy and reduced thymic output remain largely elusive. Elucidation of key pathways may pave the way for new strategies to prevent immune senescence and delay inflammatory responses.

Mitochondrial dysfunction

Mitochondrial dysfunction occurs mostly in aging tissues and cell types (including, of course, T cells) . Mitochondrial proteins were more abundant in T cells from older individuals than from younger individuals, but they were damaged by oxidative phosphorylation, suggesting that the cells accumulated a large number of dysfunctional mitochondria. The reason may be caused by the ineffective cycle of mitochondrial autophagy. Mitochondria are not only critical for bioenergetics and cellular metabolism , including maintaining the NAD/NADH ratio . Mitochondria are also signaling hubs that generate, transmit and respond to reactive oxygen species (ROS) or calcium spikes. In aging T cells, these signaling pathways are dysregulated. Mitochondrial dysfunction in T cells leads to the acquisition of a pro-inflammatory phenotype through multiple molecular mechanisms , including accumulation of inflammatory metabolites, epigenetic alterations, and post-transcriptional protein modifications . In T cells, mitochondrial decline is associated with the acquisition of a senescent phenotype. Therefore, low-dose rotenone can inhibit respiratory chain complex I in mitochondria and accelerate the immune senescence of CD4+ T cells. In addition, knockout of T cell mitochondrial transcription factor A (English abbreviation: TFAM) can lead to mitochondrial failure.

Currently, metformin is undergoing clinical trials to delay aging . Metforminenhances TFAM expression and mitochondrial function in mouse CD8+ T cells, helping to resolve Mycobacterium tuberculosis infection. Mitochondrial function recovery-enhancing strategies have been used to restore depleted TILs. GDF15 is a mitochondrial factor produced by mitochondrial stress or dysfunction. GDF15 can maintain the immunosuppressive function of Treg cells and slow down inflammation . Intervention of endocrine factors (including GDF15) may provide a new strategy for improving immunity in the elderly.

Mr. Bubu's comment: Restoring mitochondrial function may help to restore T cell dysfunction.

Genetic and Epigenetic Alterations

T cells also undergo genetic and epigenetic changes with age . Chromosomal changes accumulate in aging T cells, and there is an increased incidence of T-cell leukemia, which is more common in Japanese than in Europeans. Genome instability in T cells may be caused by mitochondrial stress, overproduction of ROS and telomere attrition and reduced activity of repair enzymes .

All major T cell subsets exhibit an age-related decrease in telomere length, which is strongly associated with chronic infection in humans, especially cytomegalovirus (CMV ) . Idiopathic pulmonary fibrosis (IPF) is the most common manifestation of short telomere syndrome in humans. Impaired T-cell immunity to CMV in IPF patients who underwent lung transplantation demonstrated that shortened telomeres impair T-cell function. Therefore, telomerase mutations may develop T-cell immunodeficiency. The closer to healthy centenarians, the longer the telomeres of T cells, the higher the activity of telomerase and the stronger the ability of cell proliferation .

Epigenetic changes may have been associated with T cell aging . It affects DNA methylation as well as histone coding and its multiple post-translational modifications, which partly explains the aging process of T cells. Age of DNA methylation was particularly high in individuals with shorter leukocyte telomere length and was associated with low levels of memory CD8+ T cells and high levels of naive CD8+ T cells. Age-related epigenetic changes in the DNA methylome have been reported to first spike in the late 30s or early 40s, at a time similar to that of women; the second peak is earlier (5-6 years later) and stronger in men, which is consistent with associated with a reduction in male life expectancy.

Mr. Bubu's comment: Whether it is genetic or epigenetic, it may cause T cell aging, which in turn affects the overall health status and even life expectancy.

Loss of protein stability

For the degradation of misfolded or aged proteins , the body is mediated by two pathways, proteolytic enzymes and autophagy . Defects in either of these lead to aging of T cells.

Autophagy is the only mechanism for the recycling of large protein aggregates and organelles in the body. Autophagosomes degrade luminal contents in large quantities by fusing with lysosomes. Autophagy tends to be deficient with age, and these factors may include:

1. Increases in nutrients (glucose and free fatty acids) and growth factors (insulin and IGF1) associated with metabolic syndrome overactivate the mTORC1 pathway that inhibits autophagy;
2. Reduced activation levels of nutrient sensors such as Sirtuin-1 due to an age-related decline in nicotinamide dinucleotide (NAD) ;
3. Reduced levels of spermidine required for hypnosis-dependent translation of autophagy-promoting proteins;
4. Reduced activation of autophagy transfection factor cascades, such as the FOXO1-TFEB axis.

Theoretically, autophagy could be reestablished by reducing caloric intake (through caloric restriction or intermittent fasting) and providing dietary supplements of NAD precursors (e.g., NMN, spermine) , thereby increasing healthspan and lifespan .

The age-dependent decline in autophagy also affects T cells. Memory T cells and Treg cells are more dependent on oxidative phosphorylation than effector T cells and are particularly susceptible to autophagy inhibition. Pharmacological inhibition of autophagy interferes with tissue-resident reprogramming of human memory CD8+ T cells . Autophagy has anti-inflammatory effects mediated at least in part by Treg cells .

Short-term administration of rapamycin ( mTORC1 inhibitor ) boosts CD8+ T memory cell immune responses to viral infection in mice and improves immune responses to influenza virus vaccine in older adults. In individuals belonging to long-lived families, CD4+ T cells showed improved activation-induced autophagic activity compared with controls. In conclusion, autophagy is an effective target against T cell senescence, and induction of autophagy can reduce inflammation while improving the sensitivity of immune responses.

Mr. Bubu's comment: It is a good idea to restore or enhance autophagy to effectively delay aging. It is a good idea to control calorie intake and intermittent diet. In addition, NAD precursors, spermine, and rapamycin are also worth studying.

Four secondary features

Decreased TCR diversity

TCR diversity changes with age, which is related to multiple factors that change over time:

1. The thymus reduces the production of naive T cells;
2. Cloning of hematopoietic cells gives some T cells a growth advantage;
3. Continuous selection of peripheral antigens;
4. Senescence of T cell subsets due to restriction of clonal expansion.

Existing evidence suggests that both internal and external factors may reduce the TCR diversity of T cells (especially in the CD8+ T effector memory CD45RA+ (TEMRA) subset) , impair immune function, and lead to a disproportionate expansion of exhausted T cells.

In aging individuals, naive T cells exhibited progressive reductions in TCRβ CDR3 length, the number of NDN insertions and non-template additions of N nucleotides, and marked changes in the physicochemical properties of the core part of the CDR3 loop. These alterations were found in CD4, CD8, RTE-enriched cells, and mature CD4 subsets of naive T cells.

The diversity of the TCR repertoire changes and partially shrinks with age . Administration of IL-7 increased the diversity of the TCR repertoire in vivo, possibly due to increased levels of naive T cell proliferation.

The imbalance between the initial T and the memory T ratio

The number of specific antigens recognized by T cells is directly proportional to the number of clones present in the initial T cell repertoire. Maintenance of the naive T cell repertoire relies on peripheral division of existing clones rather than generation of new clones . Thus, naive T cells can function as stem cells without the thymus exporting new T cells.

With age, the initial repertoire is highly differentiated and shrinks as memory cells accumulate, illustrating the depletion of the stem-like repertoire in the T cell lineage. CD8+ naive T cells exhibit reduced homeostatic proliferation compared with CD4+ naive T cells. In addition, the initial memory balance of human T cells has been studied mainly in peripheral blood, which is far more than tissue-resident T cell pools. Independent studies have shown that naive T cells in gut-associated lymphoid tissue, lymph nodes, and spleen decrease with age.

Therapeutic administration of high levels of IL-7 to humans promotes a massive increase in naive T cells in as little as 1 week. IL-7 treatment induces CD4+ and CD8+ T cell expansion in vivo, preferentially increasing T cells with distinct TCR repertoire specificities. These effects are mainly mediated by increased proliferation and survival of peripheral T cells. When homeostasis is out of balance, naive T cells differentiate into memory T cells.

Taken together, the available data suggest that highly differentiated memory T cells are enriched while naive T cells are reduced in the initial repertoire due to thymic regression, persistent antigenic stimulation, and an inflammatory environment . Memory responses produced in youth or adulthood appear to be more durable than those produced in old age

T cell exhaustion

Aging is accompanied by the accumulation of dysfunctional, terminally differentiated T cells. T cell immune responses are limited by a senescent or exhausted phenotype of T cells due to prolonged antigenic stimulation or chronic viral infection. Although both senescent and exhausted T cells are defective in TCR-triggered proliferation, they differ in molecular signaling and secretory phenotypes. Senescent T cells secrete large amounts of proinflammatory cytokines ( such as TNF and osteocalcin ) , which are associated with the senescence-associated secretory phenotype (SASP) . Senescence hallmarks of senescent T cells also include low telomerase activity and short telomeres, signs of DNA damage, resistance to apoptosis, and β-galactosidase activity.

Human CD4+ T cells and CD8+ T cells differ in their sensitivity to senescence, with CD8+ T cells acquiring an immunosenescent phenotype more rapidly . It has been reported that Treg cells age more severely than effector T cells during aging. Lentiviral infection can accelerate T cell senescence .

Inflammatory stress signals, insufficient glucose supply, or mitochondrial dysfunction may also lead to premature aging of T cells. Senescent T cells are involved in the pathogenesis of certain age-related diseases, such as cardiovascular, metabolic and neurodegenerative diseases. Phytochemicals such as polyphenols, probiotics, and omega-3 fatty acids have also been reported to reverse immune aging.

In summary, with aging, senescent T cells accumulate, with reduced immune function but increased pro-inflammatory function . Unraveling senescent T cells ( senescent lysis) may provide targets for intervention in aging and age-related diseases , including metabolic syndrome and neurodegenerative diseases .

Loss of effector T cell plasticity

CD4+ T cells can be differentiated into different subgroups, including Th1, Th2, Th9, Th17, Th22, Tfh and Treg cells. Under antigen induction, Th cells develop into different lineages. With age, T cells transition from quiescent naive T cells to terminally differentiated effector T cells, which may lead to developmental deviations, loss of plasticity, and reduced immune system responsiveness to neoantigen stimuli.

CD4+ T cells from aging mice can identify exhausted, cytotoxic and activated regulatory T cells, often with extreme anti-inflammatory and pro-inflammatory properties. Elevated circulating inflammatory cytokines (mainly IFN-β, IL-6 and IL-27) were associated. This suggests that inflammation interacts with CD4+ T cell senescence .

In centenarians, an expansion of CD4+ CTL cells associated with aging was found . In aged or mice, CD8+ cell populations are characterized by the expansion of oligoclonal and exhausted populations of T cells that secrete granzyme K (GZMK) , which stimulatessenescence in other cells , such as fibroblasts .

In short, senescence of T cells is associated with reduced plasticity and a terminally differentiated phenotype, affecting the extent of their resilience in response to neoantigen stimuli. In tumor immunology, the functional efficacy of T cell infiltration of tumors can be restored by induced pluripotent stem cell (iPSC) technology. But whether a similar approach could be chosen to restore plasticity in senescent T cells remains to be determined.

Two comprehensive features

Immunodeficiency

Decreased T cell surface receptors in the elderly, changes in the ratio between naive cells, effector cells/memory cells, and Treg cells, and the accumulation of senescent T cells may make the elderly susceptible to serious and even fatal pathogen infections. In addition, immunodeficiency may also contribute to the onset of noncommunicable diseases such as cancer or arteriosclerosis .

Indeed, the increased risk of cancer in older adults with aging may be due to a decline in immune function rather than the accumulation of somatic DNA mutations . Thus, immune escape may be a major driver of cancer during aging . Defects in T cell function lead to ineffective clearance of senescent cells, which may contribute to the accumulation of senescent cells in different tissues, although this remains to be proven.

At present, there is no clear evidence that specific functional impairment of senescent T cells affects the clearance of senescent cells and thus accelerates the aging process. Therefore, further experimental evidence is needed to confirm that defects in T cell-specific immune surveillance contribute to the aging process.

Chronic inflammation

Aging-associated chronic inflammation refers to the low-grade chronic inflammatory state that develops with age . It is characterized by the presence of high concentrations of inflammatory factors in the serum, such as C-reactive protein (CRP) , IL-6, IL-8, and TNF.

Inflammation is associated with an increased risk of several diseases and mortality associated with aging . Although inflammation was initially considered a biomarker of age-related diseases, much evidence suggests a causal relationship between inflammation and age-related tissue degeneration. Clinical trials have shown that the neutralization of some NSAIDs and IL-1 and TNF can delay the development of cardiovascular disease.

Inflammatory development has been attributed to a combination of aging defects (such as increased intestinal permeability, chronic infection, and accumulation of senescent cells) . Evidence suggests that the time-dependent degeneration of T cells directly or indirectly through the production of inflammatory factors and failure to eliminate senescent cells, affects the function of different myeloid cell types (such as macrophage subtypes) or through the regulation of intestinal permeability. Indirectly promote inflammation.

T cell metabolic stress response can accelerate inflammation. Long-term chronic inflammation can also suppress specific immune responses and reduce the effectiveness of vaccination . Interestingly, while inflammation occurs, IL-10 is also increased in older adults. IL-10, an anti-inflammatory factor that may play an important role in combating inflammation and promoting healthy aging, is produced by Tfh cells. IL-21 is critical for maintaining this balance, as IL-21-deficient mice had reduced IL-10 (and lost IL-10-producing Tfh cells) but increased IL-6 expression, suggesting that the cytokine There is a complex crosstalk with the regulation of inflammation, which is not clear.

Metformin, which has been successfully used in the long-term treatment of diabetic patients, activates the AMP-activated protein kinase signaling pathway . Metformin has been reported to improve Th17 inflammatory response by increasing autophagy of T cells and improving mitochondrial bioenergetics. Chronic, low-dose resveratrol reverses immunosenescence and inflammatory phenotypes in aged mice as it corrects age-associatedeffects of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage increase. Scientists are trying to combine different strategies, including anti-inflammatory drugs, lysis of senescent cells and immune checkpoint inhibitors, to optimally block inflammation.

Inflammation occurs in part due to dysfunctional or senescent T cells . Improving inflammation is a research hotspot to prevent the onset of aging-related diseases and the decline of immune response.

Summary

"The dead are old", as we age, the body's immune system loses the ability to respond quickly and precisely to new antigens, infections or tumor stimuli, and the ability of the immune system to generate and stimulate the differentiation of memory cells is also reduced . Not only that, but the aging immune system can also promote the occurrence of inflammation and autoimmune diseases. Senescent T cells induce persistent inflammation that accelerates the development of pathological features associated with debilitating and death in humans ( such as cardiovascular and metabolic diseases, chronic kidney disease, nonalcoholic fatty liver disease, and neurodegenerative diseases ) .

As mentioned in the article above, the characteristics of T cell aging can be divided into three types:

1. There are four main features: thymic degeneration, mitochondrial dysfunction, genetic and epigenetic alterations, and imbalances in protein homeostasis. These four main features lead to the initial damage .
2. There are four secondary features: TCR reduction, memory bank expansion, loss of effector cell plasticity, and T cell senescence. These four secondary characteristics are the result of the four main characteristics .
3. There are two combined features: immunodeficiency and chronic inflammation. These two characteristics are more specific and directly cause immune decline .

Theoretically, T cell senescence may involve endogenous immune processes, alterations in lymphoid organs, host-intrinsic metabolic or neuroendocrine factors outside lymphoid organs, increased risk of infection, and changes in gut microbiota. This means that it is difficult to distinguish the real cause of aging-related T cell dysfunction, because they are interrelated . Allogeneic tissue transfer experiment (transplantation of young T cells to old mice) , lymphoid organ transplantation between mice of different ages, allosymbiosis (ie connection of circulatory system) connection system between mice of different ages, fecal microbial transplantation, These experiments should be explored in a systematic way.

The answer to the question whether delaying T cell senescence can delay systemic aging is. Aging research is a long way to go. Therefore, emerging therapeutic approaches based on T cell immunotherapy are emerging as promising therapeutic strategies for aging-related diseases.