Telomeres are protective structures at chromosomal ends. Without the protective telomeric complex, the cell’s DNA repair machinery would recognize the ends of chromosomes as DNA double strand breaks and would constantly try to “repair”; resulting in telomere lesions that are lethal to cells. The protective caps at the end of chromosomes are composed of repetitive nucleotide sequences; TTAGGG is repeated 2,500 times in human cells. As chromosomes are replicated, telomeric ends are shortened due to the “end replication problem” referring to the difficulties of the replication machinery to attach RNA primers. Thus, with each cell division, telomeric sequences are estimated to shorten by 50bp.

Replication-associated loss of telomeric sequences has led to the concept that cells can use their telomeres as internal clocks and that telomeric length is a measure of cellular age. Most somatic cells cannot lengthen telomeres; but stem cells and lymphocytes have telomerase, a reverse transcriptase that adds telomere repeat sequences to the 3’ end. Telomerase is expressed by most cancer cells, where it secures survival despite proliferative pressure.  In telomerase+ cells, telomeres are dynamic structures and telomeric length may be less informative.

In 2000, we reported that telomeres are age-inappropriately shortened in CD4 T cells from patients with the autoimmune disease rheumatoid arthritis (RA) (Koetz et al., Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9203). This observation gave rise to the concept, that RA T cells are prematurely aged. Based on telomere length, the biologic age of RA T cells is > 20 years higher than their chronologic age.

In subsequent studies, we have investigated which cell types in RA patients are affected by this premature aging process. RA neutrophils have equally shortened telomeres when compared to neutrophils of age-matched healthy subjects, implicating the bone marrow stem cell as a target of excessive proliferative pressure and subsequent cellular aging.

Over the last decade, our research team has pursued two major questions:

Which signals/mechanisms drive accelerated aging in the immune system of patients with RA?

What are the functional consequences of premature T cells aging? Are effector functions altered in pre-aged T cells?

Answering these two questions will have a major impact on the pathogenic models for RA, will cross-fertilize the field of immune aging in healthy individuals and will enable the development of novel therapeutic interventions suppressing chronic tissue inflammation in conditions other than RA.

Recent work in the laboratory has been dedicated to the identification and characterization of mechanisms underlying the accelerated aging phenotype in RA T cells.

This work has led to the recognition that the DNA repair machinery in RA T cells has defects that directly promote cellular aging. We have identified multiple molecules that play a direct role in guarding healthy aging in T cells. Notably, several of the molecular players are intracellular metabolites and enzymes regulating bioenergetic processes. Prominent amongst the aging-associated molecules are DNA repair molecules, including the DNA repair kinase ATM and the repair nuclease MRE11A.

MRE11A has 3’ to 5’ exonucleolytic and endonucleolytic activity. Together with DNA ligases, MRE11A facilitates the joining of noncomplementary DNA ends. Our work has demonstrated that MRE11A has functions beyond DNA repair and is critically involved in telomeric maintenance and stability. Transcription and protein expression of MRE11A is highly sensitive to the aging process. MRE11A protein declines in both naïve and memory CD4 T cells with progressive age, with acceleration of the process by 20-30 years in RA patients. Overall, the nuclease is amongst the most significantly repressed genes in aged T cells (Li et al.; Immunity. 2016 Oct 18;45(4):903-916 ).  Aging-related MRE11A deficiency results in low amounts of the nuclease at telomeric ends. MRE11Alow T cells accumulate telomeric damage and have fragile telomeres, telomeres in apposition, telomeric fusion or complete telomeric loss. Given the loss of MRE11A in RA T cells, the age-inappropriate shortening of their telomeres may primarily reflect damage and fragility as opposed to proliferation-induced telomeric erosion.

The MRE11Alow phenotype in RA T cells has functional consequences. In a model system of RA, in which human synovial tissue is engrafted into immunodeficient mice, MRE11A loss-of-function induces aggressive synovial inflammation. Conversely, MRE11A gain-of-function is tissue protective and ameliorates synovitis.

These experimental data support a novel paradigm in understanding the joint inflammation that is typical for rheumatoid arthritis. Instead of emphasizing the antigens that are encountered by tissue-invading T cells that are believed to break tissue tolerance, alternate biological processes are being implicated: intactness of the telomere, regulation of cellular bioenergetics, efficiency of DNA repair, threshold setting of T cell activation. Overall, the tissue inflammation associated with autoimmunity is viewed as a loss of a cytoprotective program that deteriorates with age and fails prematurely in patients with RA.