Involvement of expanded cytotoxic and proinflammatory CD28^null T cells in primary Sjögren's syndrome

The absence of CD28 is a feature of antigen-experienced, highly differentiated and aged T cells. The pathogenicity of CD28^null T cells remains elusive in primary Sjögren's syndrome (pSS). Therefore, this study was performed to explore the characteristics of CD28^null T cells in both peripheral blood and minor salivary glands (MSGs) of pSS patients.

pSS patients and paired healthy controls (HCs) were enrolled. The phenotype of peripheral CD28^null T cells was analyzed using flow cytometry. In vitro functional assays were performed to evaluate the cytotoxic and proinflammatory effects of peripheral CD28^null T cells. In addition, polychromatic immunofluorescence staining was performed to investigate infiltrating CD28^null T cells in MSGs.

A significant expansion of peripheral CD28^null T cells was observed in pSS patients compared with HCs (p < 0.001), which were primarily CD8⁺CD28^null T cells. The proportion of peripheral CD8⁺CD28^null T cells moderately correlated with the erythrocyte sedimentation rate (r = 0.57, p < 0.01) and IgG levels (r = 0.44, p < 0.01). Peripheral CD28^null T cells had stronger capacities to secrete granzyme B and perforin, but comparable capacities to secrete IFN-γ and TNF-α than their CD28⁺ counterparts. An abundant amount of cytotoxic and pro-inflammatory CD28^null T cells was also found in MSGs. Moreover, a high expression of the chemokine receptor CXCR3 was found on peripheral and tissue-resident CD28^null T cells, with its ligands CXCL9/10 abundantly present in MSGs.

Increasing CD28^null T cells with strong cytotoxicity and proinflammatory effects were observed in both peripheral blood and MSGs from pSS patients. The precise mechanism of action and migration still needs further investigation.