CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs

Abstract

The inflammatory response regulates congestive heart failure (CHF) development. T-cell activation plays an important role in tissue inflammation. We postulate that CD28 or B7 deficiency inhibits T-cell activation and attenuates CHF development by reducing systemic, cardiac and pulmonary inflammation. We demonstrated that chronic pressure overload-induced end-stage CHF in mice is characterized by profound accumulation of activated effector T-cells (CD3+CD44high cells) in the lungs and a mild but significant increase of these cells in the heart. In knockout (KO) mice lacking either CD28 or B7, there was a dramatic reduction in the accumulation of activated effector T cells in both hearts and lungs of mice under control conditions and after transverse aortic constriction (TAC). CD28 or B7 KO significantly attenuated TAC-induced CHF development, as indicated by less increase of heart and lung weight, and less reduction of LV contractility. CD28 or B7 KO also significantly reduced TAC-induced CD45+ leukocyte, T-cell and macrophage infiltration in hearts and lungs, lowered pro-inflammatory cytokine expression (such as TNF-α and IL-1β) in lungs. Furthermore, CD28/B7 blockade by CTLA4-Ig treatment (250μg/mouse every 3 days) attenuated TAC-induced T cell activation, LV hypertrophy, and LV dysfunction. Our data indicate that CD28/B7 deficiency inhibits activated effector T-cell accumulation, reduces myocardial and pulmonary inflammation, and attenuates the development of CHF. Our findings suggest that strategies targeting T-cell activation may be useful in treating CHF.

Role of bone marrow-derived CD11c+ dendritic cells in systolic overload-induced left ventricular inflammation, fibrosis and hypertrophy

“…Interestingly, recent studies demonstrated that T cells play an important role in promoting the pressure overload-induced LV hypertrophy and dysfunction [16, 21]. Our recent study further demonstrated that chronic pressure overload causes an increase of activated effector T cells and inhibition of T-cell activation by B7 or CD28 gene deficiency can partially attenuate pressure overload-induced LV hypertrophy and dysfunction [23]. In addition, recent studies from us and others have consistently demonstrated that regulatory T cells (Tregs), a group of powerful anti-inflammatory T cells, can effectively suppress pressure overload-induced LV leukocyte and T cell infiltration and LV hypertrophy in mice [12, 22], indicating an important role of T cells in regulating LV hypertrophy and dysfunction.…”

“…Our recent study demonstrated that T-cell accumulation and activation are increased in the LV tissues in mice after chronic TAC [23]. To determine whether LV inflammation was related to an increase of DCs, we examined LV CD11c + cells and CD11c + MHCII + DCs under control conditions and 8 weeks after TAC in mice using flow cytometry analysis with the gating strategy are described in Suppl.…”

“…Since our previous data showed that TAC caused a significant increase of activated T cells in the spleen and peripheral blood in mice [23], we further examined DCs in spleen tissues and peripheral blood using flow cytometry analysis (gating strategies are presented in Suppl. Fig.…”

Mineralocorticoid Receptor Deficiency in T Cells Attenuates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction Through Modulating T-Cell Activation

“…29,30 Previous reports have shown that lessened T-cell activation is correlated with diminished cardiac inflammation in the setting of POL. 5,6 We presented that TMRKO mice manifested reduced cardiac inflammation in parallel with improved cardiac remodeling, as well as decreased T-cell accumulation and activation in the heart after POL. Particularly, cardiac expression levels of inflammatory cytokines, as well as accumulation of neutrophils and monocytes/macrophages, were both suppressed by T-cell MR deficiency.…”

“…5 Similarly, deletion or blockade of CD28 or B7, essential components of signal 2 of T-cell activation, attenuates POL-induced cardiac hypertrophy, heart failure, cardiac inflammation, and T-cell accumulation. 6 Interestingly, CD4 + T cells, but not CD8 + T cells, are critical in the transition from cardiac hypertrophy to heart failure in response to POL. 7 Therefore, it may be a feasible strategy to identify key molecules that regulate T-cell function and that ultimately intervene in cardiac hypertrophy and heart failure.…”