Skin-Resident Effector Memory CD8⁺CD28^- T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis

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.