Scurfy (Foxp3(Sf)/Y), Il2(-/-), and Il2ralpha(-/-) mice are deficient in CD4(+)Foxp3(+) regulatory T cells (Treg), but only the latter two develop inflammation in the submandibular gland (SMG), a critical target of Sjögren's syndrome. In this study, we investigated the reason that SMG of Scurfy (Sf), Sf.Il2(-/-), Sf.Il2ralpha(-/-), and the long-lived Sf.Fas(lpr/lpr) mice remained free of inflammation, even though their lymph node cells induced SMG inflammation in Rag1(-/-) recipients. A strong correlation was observed between the development of the granular convoluted tubules (GCT) of the SMG in these mice and SMG resistance to inflammation. Moreover, GCT development in Sf.Rag1(-/-) mice was not impeded, indicating a role of adaptive immunity. In the Sf.Fas(lpr/lpr) mice, this block was linked to atrophy and inflammation in the accessory reproductive organs. Testosterone treatment restored GCT expression, but did not induce SMG inflammation, indicating GCT is not required for inflammation and additional mechanisms were controlling SMG inflammation. Conversely, oral application of LPS induced SMG inflammation, but not GCT expression. LPS treatment induced up-regulation of several chemokines in SMG with little effect on the chemokine receptors on CD4(+) T cells in Sf mice. Our study demonstrates that Sf mutation affects SMG development through adaptive immunity against accessory reproductive organs, and the manifestation of SMG inflammation in Sf mice is critically controlled through innate immunity.