Deficiency of DOCK2 delays development of spontaneous uveoretinitis in a lymphopenic mouse model of colitis

Abstract

Abstract Spontaneous experimental autoimmune uveoretinitis (EAU) in double-transgenic (dTg) mice expressing retinal Hen Egg Lysozyme (HEL) and HEL-specific T cell receptor CD4 T cells is a severe CD4⁺ T cell-driven disease, occurs in 100% of dTg mice at post-partum day (p)20/21 and is accompanied by post-EAU colitis. Because DOCK2 (Dedicator of cytokinesis 2) is essential for Rac-dependent immune cell function, including T cell motility and migration from secondary lymphoid tissues, we investigated its effect on T cell behaviour in this model. dTg mice lacking DOCK2 (DOCK2 ⁻/⁻ dTg) were examined for evidence of uveitis (fundoscopy, histology and flow cytometry) and intestinal inflammation (colon length and histology). Retinal inflammation and ocular CD4⁺ T cell infiltration were assessed over time. Flow cytometry of lamina propria cells quantified CD4⁺ T cells and determined the balance of Helios + versus Helios − regulatory T cells. The eye-draining lymph nodes were also analysed for CD4⁺ T cell populations. DOCK2 ⁻/⁻ dTg mice showed delayed and attenuated uveitis. Retinal inflammation, consistently evident by p21 in DOCK2 +/+ dTg mice, and atrophy (~ p30) were absent until ~p60 and were associated with markedly reduced ocular CD4⁺ T cell infiltration. Despite profound lymphopenia, DOCK2 deficiency did not induce spontaneous colitis; colons were normal in length and lacked inflammation. Flow cytometry of lamina propria cells showed no change in overall CD4⁺ T cell numbers between DOCK2 ⁻/⁻ and DOCK2 ⁺/⁺ mice. However, the balance of Helios expression in Treg was altered, with DOCK2 ⁻/⁻ mice containing significantly higher numbers of Helios − Treg in the lamina propria compared to DOCK2 +/+ mice. In contrast, peripheral lymphoid tissues (eye-draining lymph nodes), showed disproportionately reduced CD4⁺ T cell numbers in DOCK2 ⁻/⁻ dTg mice. We conclude DOCK2 may be a potential target for control of uveoretinitis via expansion of eye-homing gut Helios − Treg.