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.


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 microm2, 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.
Stabile
Eugenio
E
Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC 20010, USA. geko50@tiscali.it
Kinnaird
Timothy
T
la Sala
Andrea
A
Hanson
Sue Kim
SK
Watkins
Craig
C
Campia
Umberto
U
Shou
Matie
M
Zbinden
Stephan
S
Fuchs
Shmuel
S
Kornfeld
Hardy
H
Epstein
Stephen E
SE
Burnett
Mary Susan
MS
D000818:Animals; D050379:Arteriolosclerosis / Q000209:etiology* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D016827:CD8 Antigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003097:Collateral Circulation / Q000276:immunology*; D004195:Disease Models, Animal; D005263:Femoral Artery; D007107:Immune System / Q000502:physiology; D019410:Interleukin-16 / Q000096:biosynthesis / Q000502:physiology*; D007511:Ischemia / Q000150:complications*; D051379:Mice; D018345:Mice, Knockout
D016827:CD8 Antigens; D019410:Interleukin-16