Salivary‐gland‐protective regulatory T‐cell dysfunction underlies female‐specific sialadenitis in the non‐obese diabetic mouse model of Sjögren syndrome

Abstract

Immune cell-mediated destruction of salivary glands is a hallmark feature of Sjögren syndrome. Similar to the female predominance in humans, female non-obese diabetic (NOD) mice develop spontaneous salivary gland autoimmunity. However, in both humans and mice it is unclear what factors contribute to the initial immune infiltration of the salivary glands. Here, we used an adoptive transfer model of Sjögren syndrome to determine if female mice harbor a sex-specific defect in salivary-gland-protective regulatory T (Treg) cells. Transfer of cervical lymph node (LN) cells from female NOD mice into sex-matched NOD-severe combined immunodeficient (SCID) recipients resulted in sialadenitis, regardless of the presence or absence of Treg cells. In contrast, transfer of cervical LN cells from male NOD mice into sex-matched NOD-SCID recipients only resulted in sialadenitis when Treg cells were depleted before transfer, suggesting that male NOD mice have functional salivary-gland-protective Treg cells. Notably, the host environment affected the ability of Treg cells to prevent sialadenitis with testosterone promoting salivary gland protection. Treg cells from male mice did not protect against sialadenitis in female recipients. Testosterone treatment of female recipients of bulk cervical LN cells decreased sialadenitis, and Treg cells from female mice were capable of protecting against development of sialadenitis in male recipients. Hence, our data demonstrate that female NOD mice develop sialadenitis through a defect in salivary-gland-protective Treg cells that can be reversed in the presence of testosterone.

Type I Interferon Signaling Is Required for Dacryoadenitis in the Nonobese Diabetic Mouse Model of Sjögren Syndrome

“…Similar to previous studies [ 7 , 10 ], castration resulted in a marked decrease in the development of dacryoadenitis ( Figure 1 A,B, isotype group, sham vs. castrated). As shown in our prior study [ 6 ], treatment with an anti-CD25 monoclonal antibody did not alter development of dacryoadenitis in non-castrated male NOD mice ( Figure 1 A, isotype-sham vs. anti-CD25-sham). Surprisingly, treatment with the anti-CD25 monoclonal antibody failed to induce dacryoadenitis in castrated male NOD mice ( Figure 1 A,B) despite a significantly decreased Treg population in Treg-depleted mice ( Figure 1 C,D).…”

“…Surprisingly, treatment with the anti-CD25 monoclonal antibody failed to induce dacryoadenitis in castrated male NOD mice ( Figure 1 A,B) despite a significantly decreased Treg population in Treg-depleted mice ( Figure 1 C,D). While the castrated, Treg-depleted mice had a slight but significantly increased proportion of Tregs compared to the sham-castrated, Treg depleted mice at the end of the experiment ( Figure 1 D), their decreased proportion of Tregs compared to the non-Treg-depleted groups was comparable to the degree of Treg depletion we previously showed to be sufficient to induce dacryoadenitis in female NOD mice [ 6 ]. This difference in proportion of Tregs in the Treg-depleted groups at take-down of the experiment may be due to a decrease in the degree of Treg depletion in the castrated group or, alternatively, to a more rapid recovery of Tregs following the transient depletion.…”

“…We recently reported that transient partial depletion of Tregs in vivo in female NOD mice using a Treg-depleting monoclonal antibody (anti-CD25 clone PC61) was sufficient to drive dacryoadenitis [ 6 ]. Castrated male NOD mice were also protected from development of dacryoadenitis [ 7 , 10 ].…”

“…While Sjögren syndrome in humans is typically associated with both lacrimal and salivary gland manifestations, NOD mice do not spontaneously develop autoimmunity of both lacrimal and salivary glands. Rather, male NOD mice spontaneously develop lacrimal gland autoimmunity, while female NOD mice spontaneously develop salivary gland autoimmunity [ 5 , 6 , 7 , 8 , 9 , 10 ]. Prior work by us and others has demonstrated that lacrimal gland disease in male NOD mice is dependent on male sex hormones [ 7 , 8 , 10 ].…”

Sex‐mediated elevation of the specialized pro‐resolving lipid mediator levels in a Sjögren's syndrome mouse model

“…Additional evidence that sex hormones may be involved comes from the observation that castrated NOD/ShiLtJ male mice display SS‐like clinical features similar to females while ovariectomized females show the opposite effect 55,56 . Testosterone treatment of female mice has been shown to reduce salivary gland inflammation 57 . Finally, Th17 cells from a C57BL/6.NOD‐ Aec1Aec2 SS‐like mouse model show increased proliferation only in females 58 .…”