Natural Killer Cells and CD4 ⁺ T-Cells Modulate Collateral Artery Development

Abstract

Objective— The immune system is thought to play a crucial role in regulating collateral circulation (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease. Here, we studied the role of lymphocytes in a murine model of hindlimb ischemia. Methods and Results— Lymphocytes, detected with markers for NK1.1, CD3, and CD4, invaded the collateral vessel wall. Arteriogenesis was impaired in C57BL/6 mice depleted for Natural Killer (NK)-cells by anti-NK1.1 antibodies and in NK-cell–deficient transgenic mice. Arteriogenesis was, however, unaffected in Jα281-knockout mice that lack NK1.1 + Natural Killer T (NKT)-cells, indicating that NK-cells, rather than NKT-cells, are involved in arteriogenesis. Furthermore, arteriogenesis was impaired in C57BL/6 mice depleted for CD4 + T-lymphocytes by anti-CD4 antibodies, and in major histocompatibility complex (MHC)-class-II–deficient mice that more selectively lack mature peripheral CD4 + T-lymphocytes. This impairment was even more profound in anti-NK1.1-treated MHC-class-II–deficient mice that lack both NK- and CD4 + T-lymphocytes. Finally, collateral growth was severely reduced in BALB/c as compared with C57BL/6 mice, 2 strains with different bias in immune responsiveness. Conclusions— These data show that both NK-cells and CD4 + T-cells modulate arteriogenesis. Promoting lymphocyte activation may represent a promising method to treat ischemic disease.

The Presence of Activated CD4+ T Cells Is Essential for the Formation of Colony-Forming Unit-Endothelial Cells by CD14+ Cells

“…The accumulating macrophages then secrete a broad array of cytokines and growth factors, which facilitate collateral development (34). These results were confirmed by Van Weel et al (35), who described a role for NK cells and CD4 ϩ T cells in arteriogenesis in knockout mice. Their data show that both NK cells and CD4 ϩ T cells modulate arteriogenesis, and they suggest that promoting lymphocyte activation may represent a promising method to treat ischemic disease.…”

Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling

“…Recent studies have suggested that regulatory T cells and NK cells may have a role in modulating postnatal neovascularization (41,42). Interestingly, in the hBMC-SCID/bg mouse model, a statistically significant difference in overall patency rates was not detected between BMC-seeded and unseeded scaffolds, which may be a reflection of the immunodeficient component of our mouse model.…”

Regulatory T Cells Modulate Postischemic Neovascularization

“…Hence, collateral growth is impaired after natural killer cell depletion and in natural killer cell-deficient mice. 9 Leukocytes trigger neovascularization through the release of several angiogenic/arteriogenic factors, including vascular endothelial growth factor (VEGF) and proinflamma-tory cytokines such as tumor necrosis factor-␣ and IL-1␤. 3,10 Finally, during the inflammatory reaction, antiinflammatory cytokines such as IL-10 and transforming growth factor-␤ (TGF-␤) are also produced and are able to modulate the neovascularization process and orchestrate the tissue response to ischemia.…”