Lymphopenia in primary Sjogren's syndrome is associated with premature aging of naive CD4+T cells

Objective To investigate peripheral lymphopenia, a frequent finding in primary Sjogren's syndrome (pSS) associated with higher disease activity and increased mortality. Methods Prospective, cross-sectional study of consecutive patients with pSS (n = 66) and healthy controls (n = 181). Lymphocyte subsets were analysed by flow cytometry, naive (CD45RA(+)) and memory (CD45RO(+)) CD4(+) T cells were purified by MACS technology. In vitro proliferation and senescence-associated beta-galactosidase (SABG) were assessed by flow cytometry. Telomere length and TCR excision circles (TREC) were measured by real-time PCR. Telomerase activity was analysed according to the telomeric repeat amplification protocols (TRAP). Results In pSS, lymphopenia mainly affected naive CD4(+) T cells. We noted a lower frequency of proliferating naive CD4(+) T cells ex vivo and decreased homeostatic proliferation in response to IL-7 stimulation in vitro. Furthermore, naive CD4(+) T cells exhibited signs of immune cell aging including shortened telomeres, a reduction in IL-7R expression and accumulation of SABG. The senescent phenotype could be explained by telomerase insufficiency and drastically reduced levels of T-cell receptor excision circles (TRECs), indicating a history of extensive post-thymic cell division. TRECs correlated with the number of naive CD4(+) T cells linking the extend of earlier proliferation to the inability to sustain normal cell numbers. Conclusion In pSS, evidence for increased proliferation of naive CD4+ T cells earlier in life is associated with a senescent phenotype unable to sustain homeostasis. The lack of naive CD4+ T cells forms the basis of lymphopenia frequently observed in pSS.