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(Circulation. 2006;113:118-124.)
© 2006 American Heart Association, Inc.

Vascular Medicine

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

Eugenio Stabile, MD; Timothy Kinnaird, MB, BCh; Andrea la Sala, PhD; Sue Kim Hanson, PhD; Craig Watkins, MD; Umberto Campia, MD; Matie Shou, MD; Stephan Zbinden, MD; Shmuel Fuchs, MD; Hardy Kornfeld, MD; Stephen E. Epstein, MD; Mary Susan Burnett, PhD

From the Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC (E.S., T.K., C.W., U.C., M.S., S.Z., S.F., S.E.E., M.S.B.); Laboratory of Molecular and Cellular Biology, IRCCS, San Raffaele, Rome, Italy, and Immunology, National Institutes of Health, Bethesda, Md (A.l.S.); Department of Medicine, University of Massachusetts Medical School, Worcester (H.K.); and Pulmonary Center, Boston University School of Medicine, Boston, Mass (S.K.H.).

Correspondence to Eugenio Stabile, MD, Laboratory of Vascular Biology, Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Suite 4B 1, 110 Irving St, NW Washington, DC 20010. E-mail geko50{at}tiscali.it

Received August 11, 2005; revision received October 25, 2005; accepted October 27, 2005.

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 µm², 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.

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