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

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; P<0.01). This resulted in greater calf muscle atrophy (mean fiber area, 785±68 versus 1067±69 μm, respectively; P<0.01) and increased fibrotic tissue content (10.8±1.2% versus 7±1%, respectively; P<0.01). Moreover, CD8 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.