Ageing, autoimmunity and arthritis: Perturbations of TCR signal transduction pathways with ageing – a biochemical paradigm for the ageing immune system

It is widely accepted that cell-mediated immune functions decline with age, rendering an individual more susceptible to infection and possibly cancer, as well as to age-associated autoimmune diseases. The exact causes of T-cell functional decline are not known. One possible cause could be the development of defects in the transduction of mitogenic signals following TCR stimulation. This T-cell hyporesponsiveness due to defects of signalling through the TCR either from healthy elderly subjects or from individuals with autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus results in an impaired ability to mount efficient immune responses and to maintain responsiveness to foreign antigens. This implies that a high proportion of autoreactive T cells might accumulate either intrathymically or in the periphery. T-cell anergy and differential TCR signalling could thus also be key players in the disruption of tolerance and the onset of autoimmune diseases. The increasing number of the elderly may lead to an increase of clinically important autoimmune diseases. We will review the signal transduction changes through the TCR–CD3 complex in T lymphocytes from healthy elderly subjects, which result in a modification of the activation of transcription factors involved in IL-2 gene expression leading to decreased IL-2 production. The putative contribution of altered T-cell signalling with ageing in the development of autoimmune diseases will be also discussed.