CD8+T Lymphocytes Regulate the Arteriogenic Response to Ischemia by Infiltrating the Site of Collateral Vessel Development and Recruiting CD4+Mononuclear Cells Through the Expression of Interleukin-16

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Abstract
Background—Previous studies have demonstrated that macrophages and CD4+T lymphocytes play pivotal roles in collateral development. Indirect evidence suggests that CD8+T cells also play a role. Thus, after acute cerebral ischemia, CD8+T cells infiltrate the perivascular space and secrete interleukin-16 (IL-16), a potent chemoattractant for monocytes and CD4+T cells. We tested whether CD8+T lymphocytes contribute to collateral vessel development and whether the lack of circulating CD8+T cells prevents IL-16 expression, impairs CD4+mononuclear cell recruitment, and reduces collateral vessel growth after femoral artery ligation in CD8−/−mice.Methods and Results—After surgical excision of the femoral artery, laser Doppler perfusion imaging demonstrated reduced blood flow recovery in CD8−/−mice compared with C57/BL6 mice (ischemic/nonischemic limb at day 28, 0.66±0.04 versus 0.87±0.04, respectively;P2, respectively;PP−/−mice displayed reduced IL-16 expression and decreased CD4+T-cell recruitment at the site of collateral vessel development. Exogenous CD8+T cells, infused into CD8−/−mice immediately after femoral artery ligation, selectively homed to the ischemic hind limb and expressed IL-16. The restoration of IL-16 expression resulted in significant CD4+mononuclear cell infiltration of the ischemic limb, faster blood flow recovery, and reduced hindlimb muscle atrophy/fibrosis. When exogenous CD8+T cells deficient in IL-16 (IL-16−/−) were infused into CD8−/−mice immediately after femoral artery ligation, they selectively homed to the ischemic hind limb but were unable to recruit CD4+mononuclear cells and did not improve blood flow recovery.Conclusions—These results demonstrate that CD8+T cells importantly contribute to the early phase of collateral development. After femoral artery ligation, CD8+T cells infiltrate the site of collateral vessel growth and recruit CD4+mononuclear cells through the expression of IL-16. Our study provides further evidence of the significant role of the immune system in modulating collateral development in response to peripheral ischemia.