Background/Purpose: CD4⁺Foxp3⁺ regulatory T cells (Tregs) are a specialized population of lymphocytes which prevent autoimmunity in normal hosts. Treg dysfunction has been implicated in autoimmunity; however results are conflicting. Sjögren syndrome is an autoimmune disease characterized by destruction of lacrimal and salivary glands resulting in profound ocular and oral dryness. In the nonobese diabetic (NOD) mouse model of Sjögren syndrome, females develop earlier and more severe sialadenitis while males develop primarily dacryoadenitis. We previously reported that female NOD mice harbor a lacrimal gland-protective Treg population (Arthritis Rheum 2011;63 Suppl 10:495).  Here, we characterize the role of sex-based Treg dysfunction in the sexually dimorphic disease manifestations in our NOD mouse-based transfer model of Sjögren syndrome.

Methods: Sjögren-like disease was induced by transfer of cervical lymph node cells, either whole or depleted of the Treg-enriched CD4⁺CD25⁺ population, to lymphocyte-deficient NOD-SCID mice, which do not develop spontaneous autoimmunity. Five to seven weeks following adoptive transfer, dacryoadenitis and sialadenitis were quantified by an experienced, blinded pathologist using a standard focus score.

Results: Transfer of whole cervical lymph node cells from NOD mice to sex-matched NOD-SCID mice recapitulated sexually dimorphic features (i.e., males develop dacryoadenitis; females develop sialadenitis). Moreover, dacryoadenitis developed in female and male recipients of sex-matched donor cervical lymph node cells depleted of Tregs. Interestingly, in a male environment, female NOD donor cervical lymph node cells (not depleted of Tregs) induce dacryoadenitis; whereas, in a female environment, male NOD donor cervical lymph node cells fail to induce dacryoadenitis unless Tregs are depleted prior to transfer.

Conclusion: These data demonstrate that females harbor a population of lacrimal gland-protective Tregs that become dysfunctional in a male environment and suggest that dacryoadenitis in males is due to an underlying lacrimal gland-specific Treg defect. Studies to identify the sex-specific factors responsible for these findings are underway.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/sex-specific-regulatory-t-cell-dysfunction-in-a-mouse-model-of-sjogren-syndrome/