Loss of IL10 Signaling Promotes TLR9-Driven Liver Dysfunction by Allowing T Cell Receptor-Mediated T Cell Activation

Deficient IL10 signaling can contribute to macrophage activation syndrome. We hypothesized that in TLR-9-mediated inflammation, blocking IL10 would increase T cell activation and worsen organ dysfunction.

C57BL/6 mice (n = 3-11/cohort) were injected with A) CpG ODN1826, a TLR9 agonist, 50μg every other day for 5 doses on days - 8 - 0 (CpGLo), B) CpG 500μg on Day 0 (CpGHi), or C) CpGHi+ IL10-R blocking antibody. OTI and OTII mice, which respectively contain CD8 and CD4 cells with transgenic T cell receptors, do not respond to antigens. Wild-type C57Bl/6, OTI, and OTII mice received CpGHi+ IL10-R. Baseline (untreated) mice were included in each experiment. Animals were sacrificed one day post-challenge.

The CpGHi cohort had lower WBC (p < 0.0001), higher ferritin (p = 0.0035) and higher ALT (p < 0.05) and lower bile acid transporter mRNA levels (p < 0.05). The CpGHi cohort had increased percentages of B cells expressing activation markers (CD80, CD86, and MHC-I, p < 0.05), of dendritic cells expressing CD86 (p = 0.03), and of CD4 (p < 0.0001) and CD8 (p = 0.025) T cells expressing CD69. Compared to CpGHi, CpGHi+ IL10-R treatment increased Nur77 expression on CD4 and CD8 T cells (p < 0.0001), did not alter innate immune cells, and was associated with worse liver function (p < 0.05). We noted significant expansion of Nur77⁺CD69⁺ CD8 T cells in OTI and OTII mice, indicating an autoreactive CD8 T cell response.

In TLR9-induced hyperinflammation, IL10 restrained a feedforward loop of innate and T cell activation. The specificity of the innate and T cell interaction is unclear and may represent an autoimmune activation of CD8 T cells.