T-Cell Aging-Associated Phenotypes in Autoimmune Disease

Abstract

The aging process causes profound restructuring of the host immune system, typically associated with declining host protection against cancer and infection. In the case of T cells, aging leads to the accumulation of a diverse set of T-cell aging-associated phenotypes (TASP), some of which have been implicated in driving tissue inflammation in autoimmune diseases. T cell aging as a risk determinant for autoimmunity is exemplified in two classical autoimmune conditions: rheumatoid arthritis (RA), a disease predominantly affecting postmenopausal women, and giant cell arteritis (GCA), an inflammatory vasculopathy exclusively occurring during the 6th-9th decade of life. Pathogenic T cells in RA emerge as a consequence of premature immune aging. They have shortening and fragility of telomeric DNA ends and instability of mitochondrial DNA. As a result, they produce a distinct profile of metabolites, disproportionally expand their endoplasmic reticulum (ER) membranes and release excess amounts of pro-inflammatory effector cytokines. Characteristically, they are tissue invasive, activate the inflammasome and die a pyroptotic death. Patients with GCA expand pathogenic CD4⁺ T cells due to aberrant expression of the co-stimulatory receptor NOTCH1 and the failure of the PD-1/PD-L1 immune checkpoint. In addition, GCA patients lose anti-inflammatory Treg cells, promoting tissue-destructive granulomatous vasculitis. In summary, emerging data identify T cell aging as a risk factor for autoimmune disease and directly link TASPs to the breakdown of T cell tolerance and T-cell-induced tissue inflammation.

Keywords: autoimmune disease; giant cell arteritis; immune aging; mitochondrial metabolism; rheumatoid arthritis; tissue invasiveness; treg aging; vasculitis.

FIGURE 1

T-cell Aging-Associated Phenotypes (TASP). T cell aging leads to profound changes in the composition of the T cell pool. Major determinants of T cell aging include the dwindling generation of new T cells in face of continuous attrition and the stress imposed by acute and chronic antigen exposure, progressive differentiation and homeostatic proliferation. As naïve T cell populations shrink, the spectrum of phenotypically and functionally defined T cell subsets expands. Functional adaptations occur in three major domains: with age, T cells become more mobile and tissue invasive; with age, T cells differentiate into effector populations that are cytokine hyperproducers and possess cytotoxic functions; with age, regulatory T cells (Treg) deteriorate, allowing for unopposed effector responses. The assembly of T cell phenotypes in the aged T cell pool biases towards less specific and more inflammatory immunity. T cell aging-associated phenotypes (TASP) are enriched in patients with late-onset autoimmune diseases and have been implicated in pathogenic tissue inflammation, identifying the T cell aging process as a risk factor for the loss of self-tolerance.

FIGURE 2

Signaling pathways in pathogenic T cells. Several signaling pathways have been implicated in mediating pathogenic T cell function in autoimmune tissue inflammation. In the autoimmune disease rheumatoid arthritis (RA), which affects individuals with a prematurely aged immune system, mitochondrial-ER communication is faulty due to insufficient generation of the amino acid aspartate, resulting in expansion of ER membranes and excessive production of the cytokine TNF-alpha. Also, in RA T cells, mitochondrial repair is impaired due to lacking activation of AMPK and unopposed activation of mTORC1 on the lysosomal surface. Mistrafficking of AMPK to the lysosome is a consequence of insufficiency in the enzyme N-myristoyltransferase 1(NMT1), which is responsible for posttranslational modification of AMPK. In giant cell arteritis, a strictly aging-associated autoimmune and autoinflammatory disease, persistent signaling through the JAK/STAT pathway and the CD28 pathway have been mechanistically connected to pathogenic immune responses in the inflamed tissues.

FIGURE 3

Metabolic pathways underlying enhanced cell motility in aged T cells. With progressive age, T cells become hypermobile and tissue invasive, facilitating their role in tissue inflammation. In T cells from prematurely aged patients with the autoimmune disease rheumatoid arthritis, mechanisms underlying the propensity of T cell invasiveness have been defined. Metabolic restructuring shifting glucose away from glycolytic breakdown to the pentose phosphate pathway promotes NADPH production and lipogenesis. Accumulation of intracellular lipids is enhanced by mitochondrial failure and disruption of beta oxidation. Lipid droplets serve as reservoirs for membrane formation, equipping the cells with invasive membrane structures and turning T cells into highly invasive, inflammatory effector cells.

FIGURE 4

Death pathways in aged T cells. With age, T cells are at increasing risk to die, aggravating the need for T cell replenishment but also exposing the tissue environment to an inflammatory nidus. Misregulation of histone production as well as accumulation of damaged telomeric ends have been implicated in disturbing proper cell cycle progression and inducing T-cell death. Mitochondrial insufficiency serves as a major cause of lacking ATP production, depriving the cells of the bio-energy needed for survival. The inability of aging T cells to maintain stability of the mitochondrial genome has been mechanistically linked to the leakage of mtDNA into the cytosol, the activation of the inflammasome and the triggering of pyroptotic death. T cell pyroptosis purges T-cell reservoirs in lymph nodes and induces aggressive inflammation in peripheral tissues sites.

FIGURE 5

Signaling pathways in aged T cells. A hallmark of the T cell pool in the older adult is the emergence of T cell phenotypes that are functionally highly differentiated, possibly due to the replicative stress imposed by chronic antigenic stimulation and the cytokine milieu. Some T cell subpopulations progress towards end-differentiation. Multiple signaling pathways outlined in this scheme have been implicated in mediating cytokine- and antigen-derived signals and in determining the response pattern of the T cell.

FIGURE 6

Treg cell failure in aging. Subtle and frank inflammatory states of the aging host have been attributed to a failure of immunosuppressive T regulatory (Treg) cells. Treg cells rely on an array of mechanisms targeting and suppressing effector T cells. CD8⁺ Treg cells function by releasing immunosuppressive exosomes that contain NOX2. Numbers and functional competence of such CD8 Treg cells decline with progressive age in healthy individuals, a process aggravated in the age-associated autoimmune disease giant cell arteritis. In aging CD8⁺ Treg cells, aberrant expression of NOTCH4 redirects the trafficking of intracellular vesicles, essentially disrupting the release of immunosuppressive exosomes. Notch4 signaling targets multiple genes that guard the intracellular vesicle machinery, including RAB5, RAB7 and RAB11. Consequently, early lysosomes are directed towards the recycling pathway, trapping NOX2 in the cell, while formation of multivesicular bodies (MVB) and exosome release are suppressed.