Abstract 138: Deficiency of CD11a Reduces CD8+ T-Cell Activation and Proliferation in Adipose Tissue of Obese Mice

Abstract

T cells, particularly CD8 + T cells, are major participants in obesity-linked adipose tissue (AT) inflammation. CD11a, a β 2 -integrin, is crucial for T cell adhesion and interactions with antigen-presenting cells. It has been shown that stimulation of CD11a lowered the threshold of T cell activation, yet the role of CD11a in T cell activation in AT remains unknown. We used CD11a -/- mice to test the hypothesis that CD11a deficiency reduces CD8 + T cell activation in AT. Mice fed high-fat diet for 3 months were used as an obesity model, with mice on normal diet as lean controls. CD8 + T cells and related cytokines were examined in AT by flow cytometry or quantitative RT-PCR. Compared to lean wild-type (WT) mice, obese WT mice had increased numbers of activated CD8 + T cells, with higher proportions of CD11a high CD8 + memory T cells, CD44 + CD62L - effector memory CD8 + T cells and CD44 + CD69 + effector CD8 + T cells; and increased mRNA levels of granzyme B and IFN-γ in AT. Compared to obese WT, obese CD11a -/- mice had lower proportions of CD44 + CD62L - effector memory CD8 + T cells and CD44 + CD69 + effector CD8 + T cells, and decreased mRNA levels of granzyme B and IFN-γ (P<0.01), implying decreased activation of CD8 + T cells. IL-2, IL-12 and IL-18 levels were increased in AT of obese WT compared to that of leans, and were lower in AT of obese CD11a -/- mice than that of obese WT. In vitro treatment with IL-2, IL-12 and IL-18 induced proliferation and expression of IFN-γ and CD69 in CD8 + cells isolated from AT of WT mice. Compared to those from WT mice, CD8 + T cells from AT of CD11a -/- mice showed decreased response to cytokine stimulation with fewer cells expressing IFN-γ (7.0±1.1% in CD11a -/- vs. 11.3±1.1% in WT, n=3-5/group, P<0.05). In addition, using Edu labeling techniques, we studied proliferation of CD8 + T cells in AT in vivo. At 3 hours after intraperitoneal injection of Edu, no Edu + T cells appeared in blood but we found CD8 + /Edu + T cells in AT of WT mice, indicating CD8 + T cells proliferated in AT. Compared to obese WT mice, obese CD11a -/- mice had decreased proportion of proliferating CD8 + T cells in AT (1.3±0.4% in CD11a -/- vs. 2.4±0.1% in WT, n=3/group, P<0.01). In conclusion, we demonstrated that CD11a played a crucial role in CD8 + T cell activation and proliferation in AT associated with obesity.