T-cell aging in rheumatoid arthritis

Abstract

Purpose of review: With progressive age, the immune system and the propensity for abnormal immunity change fundamentally. Individuals greater than 50 years of age are not only more susceptible to infection and cancer, but also at higher risk for chronic inflammation and immune-mediated tissue damage. The process of immunosenescence is accelerated in rheumatoid arthritis (RA).

Recent findings: Premature T-cell senescence occurs not only in RA, but also has been involved in morbidity and mortality of chronic HIV infection. Senescent cells acquire the 'senescence-associated secretory phenotype', which promotes and sustains tissue inflammation. Molecular mechanisms underlying T-cell aging are beginning to be understood. In addition to the contraction of T-cell diversity because of uneven clonal expansion, senescent T cells have defects in balancing cytoplasmic kinase and phosphatase activities, changing their activation thresholds. Also, leakiness in repairing DNA lesions and uncapped telomeres imposes genomic stress. Age-induced changes in the tissue microenvironment may alter the T-cell responses.

Summary: Gain-of-function and loss-of-function in senescent T cells undermine protective immunity and create the conditions for chronic tissue inflammation, a combination typically encountered in RA. Genetic programs involved in T-cell signaling and DNA repair are of high interest in the search for underlying molecular defects.

Figure 1. Senescence-associated secretory phenotype (SASP) and tissue damage

Cells that enter the senescence program slow cell cycle progression and eventually stop proliferating. However, proliferative arrest is not associated with functional silence. Rather, senescent cells acquire the senescence-associated secretory phenotype (SASP) characterized by the secretion of proteins, such as cytokines, through which they regulate neighboring cells and tissues. SASP proteins typically elicit an inflammatory response. Cells and tissue structures potentially exposed to senescent T cells are shown.

Figure 2. Mechanisms of T Cell Aging

With progressive age, the T cell compartment undergoes profound changes induced by slowing T cell replenishment, replicative stress and chronic antigen-specific and nonspecific stimulation. Three major mechanisms have been implicated in the altered T cell functionality of the elderly and of individuals affected by premature immunosenescence. Repertoire contraction results from uneven clonal expansion and restricts T cell diversity. Recently, several molecular networks have been discovered which rewire the signaling apparatus of senescent T cells, leading to inappropriate responsiveness. Inefficiencies in DNA repair have a major impact on T cell survival, and possibly T cell differentiation, as they lower the apoptotic threshold and impose chronic genomic stress.