Bi-Directional Activation Between Human Airway Smooth Muscle Cells and T Lymphocytes: Role in Induction of Altered Airway Responsiveness

Abstract

Because both T lymphocyte and airway smooth muscle (ASM) cell activation are events fundamentally implicated in the pathobiology of asthma, this study tested the hypothesis that cooperative intercellular signaling between activated T cells and ASM cells mediates proasthmatic changes in ASM responsiveness. Contrasting the lack of effect of resting human T cells, anti-CD3-activated T cells were found to adhere to the surface of naive human ASM cells, increase ASM CD25 cell surface expression, and induce increased constrictor responsiveness to acetylcholine and impaired relaxation responsiveness to isoproterenol in isolated rabbit ASM tissues. Comparably, exposure of resting T cells to ASM cells prestimulated with IgE immune complexes reciprocally elicited T cell adhesion to ASM cells and up-regulated T cell expression of CD25. Extended studies demonstrated that: 1) ASM cells express mRNAs and proteins for the cell adhesion molecules (CAMs)/costimulatory molecules, CD40, CD40L, CD80, CD86, ICAM-1 (CD54), and LFA-1 (CD11a/CD18); 2) apart from LFA-1, ASM cell surface expression of the latter molecules is up-regulated in the presence of activated T cells; and 3) pretreatment of ASM cells and tissues with mAbs directed either against CD11a or the combination of CD40 and CD86 completely abrogated both the activated T cell-induced changes in expression of the above CAMs/costimulatory molecules in ASM cells and altered ASM tissue responsiveness. Collectively, these observations identify the presence of bi-directional cross-talk between activated T cells and ASM cells that involves coligation of specific CAMs/costimulatory molecules, and this cooperative intercellular signaling mediates the induction of proasthmatic-like changes in ASM responsiveness.

Coexpression of TGF-β1 and IL-10 Enables Regulatory T Cells to Completely Suppress Airway Hyperreactivity

“…Clearly, further research is needed into the mechanisms of AHR protection by IL-10, especially to investigate whether IL-10 directly acts on effector T cells or via APCs (39,40) and whether there are direct effects of TGF-␤1 and IL-10 on airway smooth muscle cells (ASM). Both cytokines have been shown to inhibit chemokine expression in ASM (41)(42)(43) and, in humans, adhesion of T lymphocytes to ASM has been found to increase AHR (44).…”

Treating asthma means treating airway smooth muscle cells

“…Integrins (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and CD44 are important for the adhesion of T-cells to ASM cells; adhesion between activated T-cells and ASM cells leads to DNA synthesis in the ASM cells [36]. Major histocompatibility complex (MHC) class II and the co-stimulatory molecules CD40 [37,38], CD80 and CD86 [39] are also present on ASM cells. Despite the expression of MHC class II, ASM cells are not able to present antigen [38].…”

CD40 Signaling and Plaque Instability

“…(ICAM)-1, [17][18][19]27 whereas CD40 ligation on M⌽ triggers LFA-1 and ICAM-1 expression (Table 2 and Figure 2A). 38 Notably, stimulation with CD40L enhanced the adhesion of T lymphocytes to cultured ECs, but diminished that of neutrophils, a cell type not commonly detected within undisrupted human atheroma.…”

“…Although it was originally discussed controversially, several groups have subsequently confirmed the expression of CD40L on nonlymphocytic cell types (Table 1). [22][23][24][25][26][27] Both receptor and ligand, expressed on cultured ECs, SMCs, and M⌽, are functional, mediating the various proatherogenic processes outlined below (Table 2). In additional studies, our group demonstrated expression of CD40 and CD40L in atheromatous tissue of hypercholesterolemic mice with a staining pattern similar to that observed in humans.…”