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.

Automated summary

In primary Sjogren's syndrome (pSS), peripheral lymphopenia is associated with decreased proliferation and signs of immune cell aging in naive CD4(+) T cells. Shortened telomeres, reduced telomerase activity, and low levels of T-cell receptor excision circles (TRECs) suggest a history of extensive post-thymic cell division. This senescent phenotype in naive CD4(+) T cells may contribute to the inability to sustain cell numbers and ultimately leads to lymphopenia in pSS.