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

Summary 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. In the non‐obese diabetic mouse model of Sjögren syndrome, salivary gland inflammation occurs spontaneously in females but not males. Here we show that testosterone is protective, and, in an adoptive transfer model, we show that regulatory T cells are capable of preventing salivary gland inflammation in male but not female recipients. Thus, female‐specific salivary gland autoimmunity is associated with a defect in salivary‐gland‐protective regulatory T cells.