Abstract
Loss of CD28 expression by CD8(+) T cells occurs with age and during chronic inflammatory conditions. CD8(+)CD28(-) T cells are a heterogeneous cell subpopulation whose function ranges from immunosuppressive to effector. Here we analyzed the role of CD8(+)CD28(-) T cells in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by autoimmunity, vasculopathy, and extensive cutaneous and visceral fibrosis. We show that the frequency of CD8(+)CD28(-) T cells is increased in the blood and affected skin of SSc patients, independent of patient age, and correlates with the extent of skin fibrosis. We found that most skin-tropic CD8(+)CD28(-) T cells are resident in the skin lesions of patients in the early stage of the disease, exhibit an effector memory phenotype, and present a strong cytolytic activity ex vivo. Skin-resident and circulating SSc CD8(+)CD28(-) T cells produce high levels of the profibrotic cytokine IL-13, which induces collagen production by normal and SSc dermal fibroblasts. Thus, our findings indicate that CD8(+)CD28(-) T cells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage of SSc skin disease.