Abstract 93: Natural CD4+CD25+ Regulatory T Cells Control the Development and Complications of Abdominal Aortic Aneurysm in Mice

Abstract

Abdominal aortic aneurysm (AAA) is characterized by a prominent inflammatory cell infiltrate and local destruction of extracellular matrix. Following the acute phase, the inflammatory infiltrate is predominately composed of T lymphocytes and macrophages. We have previously reported that inhibition of Th1 or Th2 cell responses had no effect on the development or the complications of experimental murine AAA. We hypothesized that another subset of T cell, natural Treg cells (Tregs), plays a role in the pathophysiology of AAA.

Male C57Bl/6 mice were infused with Angiotensin II (1μg/kg/mn) for 28 days using osmotic pumps. A control group received non-immune isotype-matched IgG antibody (n=20) and a group received anti-CD25 antibody (n=20) every 10 days that depleted more than 95% of Tregs in lymphoid organs. Treg depletion induced AAA rupture (15% vs 0%, P<0.05) and more severe AAA stages compared to control mice (P<0.01). Histological analysis showed an increase of elastin degradation (mean layer number 2.5 vs 5.6, P=0.01) and an increase of T cell accumulation in the adventitia of Treg-depleted mice (2816 vs 330 μm2, P<0.01).

CD28 or B7 deficiency leads to a profound reduction in Treg cells. We infused Angiotensin II into C57Bl/6 CD28+/+ (n=17), CD28^-/- mice (n=11) or B7^-/- mice (n=16). CD28 or B7 deficiency did not alter the pressor response to Angiotensin II. CD28 and B7 deficiency induced an increase of AAA incidence compared to control mice, respectively 68%, 72%, and 10%, P<0.001. Moreover, CD28 and B7 deficiency induced 20% of AAA rupture whereas no rupture was observed in control mice. In another set of experiments, transfer of Tregs (3x106 cells) into CD28^-/- mice abolished AAA rupture (0% vs 15%, P<0.05) and significantly reduced AAA severity (P<0.01). Moreover, Treg transfer decreased elastin degradation (mean layer number 3.7 vs 2.5, P=0.04) and T cell infiltration in the adventitia (390 vs 2747 μm2, P<0.01).

Conclusion: We have shown for the first time that natural regulatory T cell protected against AAA development and rupture.