Abstract 005: Axl Controls Survival of the CD4+ T Lymphocytes in Salt-dependent Hypertension

Abstract

Introduction: Axl, a receptor tyrosine kinase, is required for vascular and immune cell survival. We sought to investigate the effects of Axl on T lymphocyte survival during deoxycorticosterone acetate (DOCA)-salt hypertension in mice. Methods and Results: We found significant reduction in systolic blood pressure (BP) after 5-6 weeks of DOCA-salt in RAG1-/- mice after adoptive transfer of CD4+ T cells from Axl knockout (Axl-/- →RAG1-/-) compared to transferred CD4+ T cells from wild type (Axl+/+ →RAG1-/-) mice. Media area of the mesenteric artery was significantly lower in Axl-/- →RAG1-/- (4.2±0.7x10 3 m 2 ) vs. Axl+/+ →RAG1-/- (6.0±0.9x10 3 m 2 ) or Axl+/+ (6.8±0.6x10 3 m 2 ) mice. There was significant decrease in interferon gamma production by the T cells from Axl-/- (396±23 ng/mL) compared to Axl+/+ (512±42 ng/mL) after T h 1-priming. The number of carboxyfluorescein succinimidyl ester-positive cells in 6 th division was dramatically declined in Axl-/- (~0.3%) vs. Axl+/+ (~1.8%) in culture. Accordingly, we found lower number of lymphocytes in blood from Axl-/- (4.5±0.7x10 9 ) compared to Axl+/+ (7.8±0.7x10 9 ) mice. Blood leukocyte apoptosis was 2.5-fold higher in Axl-/- mice. We next investigated repopulation capacities of the hematopoietic cells from Axl-/- vs. Axl+/+ mice. There was significant decrease in Axl-/- CD3+ T cells (21±3 %) than Axl+/+ (49±3 %) in spleen after 8 weeks of competitive repopulation of bone marrow-derived cells. However, we found even greater reduction of Axl-/- T lymphocytes (15±1 %) vs. Axl+/+ T lymphocytes (52±6 %) in peripheral blood after 8 weeks of competitive repopulation. Finally, percentage of apoptotic cells was the greatest in the media (20±7 %) and adventitia (13±5 %) from Axl-/- →RAG1-/- mice compared to vascular apoptosis (6-14 % in media; and 6-9 % in adventitia) in other groups after 6 weeks of DOCA-salt. Conclusions: Our data suggest that Axl-dependent survival of the T lymphocytes is crucial for the late increase in BP in DOCA-salt hypertension.