Our long term goal is to develop effective treatments for interstitial lung disease in systemic sclerosis (SSc), based upon understanding mechanisms of lung fibrosis in these patients. Our working model is that chronic activation of type 2 CD8+ T cells is a critical event that leads to fibrosis and loss of lung function in SSc. We speculate there are both T cell requirements and fibroblast requirements for fibrosis to occur. The T cells must make profibrotic cytokines in excess of anti-fibrotic cytokines. They must deliver costimulatory signals to fibroblasts to augment the effects of the profibrotic cytokines. The fibroblasts must be responsive to the cytokines and costimulatory signals. Type 2 cytokines that these CD8+ T cells secrete, such as IL-4 and IL-4delta2 are profibrotic. We speculate that the effectiveness of type 2 cytokines in promoting fibrosis is aided by the nature of the CD8+ T cell itself. Activated CD8+ T cells release molecules, such soluble Fas ligand (FasL), that are cytolytic to some cells but stimulate collagen production by fibroblasts. Activated CD8+ T cells display ligands on their cell surface, such as CD40L and FasL, that may deliver costimulatory signals to fibroblasts to increase production of collagen when exposed to type 2 cytokines. This novel model provides a link between activation of the immune system, in particular type 2 CD8+ T cells, and fibrosis in SSc. Our overall hypothesis is that chronic activation of effector functions of type 2 CD8+ T cells causes lung fibrosis in SSc by stimulating collagen production by fibroblasts. The detailed specific aims given below. 1. Determine whether activation of CD8+ T cells to produce type 2 cytokines and have activated cytolytic machinery in the lungs of SSc patients predicts increased collagen production by lung fibroblasts and worsening restrictive lung function. 2. Identify the receptors and intracellular signaling pathways that lead to increased collagen production by lung fibroblasts activated with IL-4 and IL-4delta2, an alternative splice variant of IL-4. 3. Determine whether coexposure of fibroblasts to other T cell cytokines (interferon-gamma) or engagement of costimulatory molecules on fibroblasts (CD40, Fas) modifies IL-4 and IL-4delta2 induced collagen production by lung fibroblasts. These studies will address our hypothesis and help refine this model of mechanisms of lung fibrosis in SSc. The findings could help develop novel therapeutic approaches in SSc patients with lung disease.
