Senescent T Cells as a Contributing Cause of Age-Related Autoimmunity

The more familiar autoimmune conditions, such as rheumatoid arthritis, are not all that age-related. Like cancer in young adults, they are a rare and unlucky happenstance, a form of most likely random cellular malfunction that spreads far enough to cause major problems. In later life, however, there occur a wide range of less familiar, less categorized, and comparatively poorly understood autoimmune conditions. It is an area of active research and many unknowns - look at just how recently type 4 diabetes was identified, for example.

These age-related autoimmunities arise from the chaotic failure of the immune system in late life. Cells fall into a variety of unhealthy states, malfunctioning cells dominate over useful cells, the immune system as a whole flails, producing chronic inflammation while failing at its primary tasks, and the supply of new competent immune cells diminishes dramatically. The publication here considers just one type of problem immune cell, those that have become senescent. This, fortunately, is an area in which solutions lie just around the corner. There is every reason to believe that senescent immune cells will be just as vulnerable to destruction by senolytic therapies as any other kind of senescent cell. If they are destroyed, they will cause no further harm, and the patient will be in a better position.

Immune aging (immunosenescence) is characterized by the reduced competence of acquired immunity, leading to increased susceptibility to infection as well as decreased vaccination efficiency. Recent accumulating evidence indicates that immunosenescence underlies an increased proinflammatory trait with age, including various chronic inflammatory and metabolic disorders, such as atherosclerosis and diabetes mellitus, as well as an increased risk for autoimmunity. Cellular senescence is characterized by irreversible arrest of proliferation, grossly altered gene expression, and relative resistance to apoptosis. Notably, senescent cells are often metabolically active and may become foci of host reactions in tissues by secreting various inflammatory factors. The features and consequences of cellular senescence in T cells in the immune system, however, remain elusive.

One of the most prominent changes occurring in the immune organs with age is an early involution of the thymus. The thymus is a central immune organ to support T cell development and establish T cell self-tolerance. T cell generation in the thymus sharply declines after the juvenile stage, eventually replaced almost entirely by fat tissues at later stages of life. In concordance with the decrease of T cell genesis, the peripheral naïve T cells are gradually reduced with age. Although the peripheral T cell pool is well maintained in aged individuals, the population shows a steady increase in the proportions of memory phenotype (MP) T cells.

We reported that a unique PD-1+ MP CD4+ T cell population is increased with age, now termed senescence-associated (SA-) T cells. The SA-T cells show characteristic signs and features of cellular senescence and emerge as follicular T cells in spontaneous germinal centers (GCs) that occur in aged mice. Spontaneous development of GCs is a hallmark of systemic autoimmune diseases, and among a number of changes in immune function with age is an increasing risk for autoimmunity.



I rather suspect Gudkov is correct and SAMs and other senescent immune cells are the big reason senescent cells accumulate in the first place. Selective destruction or reprogramming are both possible solutions to this.

Posted by: Steve Hill at May 25th, 2018 7:22 AM

@Steve Hill
That's a plausible theory. It you have specialized cleanup system that can care about various sizes cells then you don't have to kill each kind separately.

On the other hand reducing the burden to cleanup can reenvigorate the cleanup system too.

Many times the body has paradoxical pathways. So only the experiment can tell

Posted by: Cuberat at May 25th, 2018 8:04 AM
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