Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity - catalysts of autoimmunity and chronic inflammation

Abstract

Rheumatoid arthritis (RA), like many other autoimmune syndromes, is a disease of adults, with the highest incidence rates reported in the elderly. The immune system undergoes profound changes with advancing age that are beginning to be understood and that need to be incorporated into the pathogenetic models of RA. The age-related decline in thymic function causes extensive remodeling of the T-cell system. Age-dependent changes in T-cell homeostasis are accelerated in patients with RA. The repertoire of naive and memory T cells is less diverse, possibly as a result of thymic insufficiency, and it is biased towards autoreactive cells. Presenescent T cells emerge that are resistant to apoptosis and that often expand to large clonal populations. These cells are under the regulatory control of nonconventional costimulatory molecules, display potent effector functions, and appear to be critical in the synovial and extra-articular manifestations of RA.

Figure 1

Replicative stress and contraction of TCR diversity. (a) With normal aging, peripheral T cells develop progressive telomeric erosion as evidence of replicative stress. (b) Frequencies of TCR excision circle (TREC)-positive T cells decline as a consequence of thymic dysfunction and cumulative peripheral turnover. Both processes are accelerated in patients with rheumatoid arthritis (RA). (c) The TCR repertoire of naive T cells in RA (light-shaded area) is markedly contracted compared with age-matched controls (dark-shaded area). Individual naive T cells in RA are present at higher frequencies and are of larger clonal sizes, resulting in a lower number of different TCRs. bp, base pairs.

Figure 2

Replicative senescence and shifts in gene expression. Cumulative replication of T cells is associated with telomeric erosion and loss of CD28 and CD40L expression, consistent with cellular senescence. Presenescent CD4⁺ T cells gain effector functions such as high production of cytokines and cytotoxic ability through a perforin/granzyme mechanism. These cells are under the regulatory control of MHC class I-recognizing receptors, such as killer immunoglobulin-like receptors (KIRs), that can provide costimulatory signals or, if coexpressed with the appropriate adapter molecule DAP12, form an independent, fully competent recognition unit.

Figure 3

Pathomechanisms in rheumatoid arthritis. The diagram illustrates how aging, altered T-cell homeostasis, and cellular senescence may be involved in the pathogenic events leading to rheumatoid arthritis.