Regulatory T Cells Promote Apelin-Mediated Sprouting Angiogenesis in Type 2 Diabetes

Abstract

The role of CD4 T cells in the ischemic tissues of T2D patients remains unclear. Here, we report that T2D patients' vascular density was negatively correlated with the number of infiltrating CD4 T cells after ischemic injury. Th1 was the predominant subset, and Th1-derived IFN-γ and TNF-α directly impaired human angiogenesis. We then blocked CD4 T cell infiltration into the ischemic tissues of both Lepr and diet-induced obese T2D mice. Genome-wide RNA sequencing shows an increased proliferative and angiogenic capability of diabetic ECs in ischemic tissues. Moreover, wire myography shows enhanced EC function and laser Doppler imaging reveals improved post-ischemic blood reperfusion. Mechanistically, functional revascularization after CD4 coreceptor blockade was mediated by Tregs. Genetic lineage tracing via Cdh5-CreER and Apln-CreER and coculture assays further illustrate that Tregs increased vascular density and induced de novo sprouting angiogenesis in a paracrine manner. Taken together, our results reveal that Th1 impaired while Tregs promoted functional post-ischemic revascularization in obesity and diabetes.

Regulatory T-cells are required for neonatal heart regeneration

“…For instances, Burzyn et al reveal that Treg directly promote activation of satellite cells and regeneration of skeletal muscle via secretion of amphiregulin 9 ; Arpaia et al demonstrate that Treg facilitate tissue repair after influenza infection 12 ; Dombrowski et al unveil that Treg promote differentiation of oligodendrocytes and regeneration of myelin in the central nervous system 14 ; and Ali et al uncover that Treg facilitate proliferation and differentiation of hair follicular stem cells in skin 11 . More recently, we have also showed that Treg promote regeneration of blood vessels in the peripheral artery system after ischemic injury in type-2 diabetes 15 . In fact, targeting T-cells for tissue regeneration offers unappreciated advantages such as specificity towards autoantigens released during injury.…”

“…There was a significant increase in %CD4 + FOXP3 + Treg among CD4 + T-cells (Fig 3B) or in absolute number of CD4 + FOXP3 + Treg per mg tissue (Fig 3C) at day 7 post CI compared to sham. We then depleted CD4 + CD25 hi FOXP3 + Treg via the lytic anti-CD25 antibodies (clone PC61) as previously described (Fig 3D, Fig S2) 15,19 . Treatment with PC61 significantly increased cardiac fibrosis (Fig 3E, F) and COLA1 deposition (Fig 3G); and significantly reduced cTnT + myocardium in the infarct zone (Fig 3G, H) and lessened Ki67 + cTnT + proliferating cardiomyocytes in the border zone at day 28 post CI (Fig 3I, J).…”

“…Mechanistically, Treg can directly activate skeletal muscle progenitors/satellite cells via amphiregulin 9 or stimulate hair follicle stem cells via Notch signaling 11 . Moreover, we have also reported that Treg directly promote endothelial cell proliferation and indirectly inhibit activation of conventional CD4 + T-cells that impair vascular regeneration after ischemic injury in type-2 diabetes 15 .…”

“…In fact, targeting T-cells for tissue regeneration offers unappreciated advantages such as specificity towards autoantigens released during injury. Indeed, we have observed that the therapeutic effect of Treg in vascular regeneration was only localized in the ischemic but not non-ischemic tissue 15 .…”

“…Long recognized as potent suppressors of the immune system, CD4 + regulatory T-cells (Treg) are recently rediscovered as direct or indirect regulators of organ regeneration 8 . We and others have showed that Treg promote repair of skeletal muscle 9,10 , skin 11 , lung 12 , bone 13 , central nervous system 14 and peripheral vascular system 15 after injury. Treg are recruited in response to neoantigens to damaged tissues for resolution of inflammation and regulation of innate immune response 16 .…”