T Cell Homeostasis and Repertoire Contraction in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is not limited to chronic articular inflammation, but patients have alterations in their global immune system in line with the clinical experience of significant systemic disease. Specifically, RA patients frequently have clonal T cell populations in the circulation that characteristically lack the expression of the CD28 molecule. Here, we propose that RA patients have a defect in T cell generation that results in the contraction of the T cell repertoire and eventually in the emergence of CD28^null clonal T cells. We have determined the diversity of the peripheral CD4 T cell repertoire by determining the frequencies of arbitrarily selected T cell receptor (TCR) β-chain sequences. Healthy individuals displayed a highly diverse repertoire, with a median frequency of individual TCR β-chain sequences of 1 in 2.4 × 10⁷ CD4 T cells. In RA patients, the median TCR β-chain frequency was 10-fold increased. The loss in TCR diversity was not limited to CD4 memory T cells but also involved naive T cells, suggesting an abnormality in T cell repertoire formation and not a consequence of antigen recognition in the synovium. Also, control patients with chronic inflammatory disease such as hepatitis C expressed a diverse repertoire. In further support for this concept, telomere length studies indicated an increased replicative history of peripheral CD4 T cells in RA patients. Lymphocyte telomeres were age-inappropriately shortened with almost complete telomere erosion at an age of less than 40 years. Again, naive T cells were predominantly affected, and their capacity to undergo clonal burst after stimulation was about 10-fold reduced. These data are consistent with a premature exhaustion of lymphopoiesis in RA that may contribute to the autoimmune response as well as to the immunodeficiency in these patients and has important implications for their clinical management.