4.1.6. Cytotoxic T Cells/ CD8<sup>+</sup> T Lymphocytes (CTLs)

CTLs are best known for their destruction of virally infected and tumor cells. They produce the pro-inflammatory effector cytokines TNF-α or IFN-γ. The effector function of CD8<sup>+</sup> T cells follows recognition by the T lymphocyte T-cell receptor of major histocompatibility complex class I (MHC I) molecules loaded with the relevant antigenic peptide, expressed at the surface of the target cells. Due to their lytic capacity, these cells represent key effectors in various autoimmune diseases [172]. Tissue resident memory CD8<sup>+</sup> T cells act as mediators of SG damage in murine models of SS but the pathogenic significance of CD8<sup>+</sup> T cells is unclear as limited studies have been performed to illuminate their role. CD8<sup>+</sup> T cells have been observed within labial SGs infiltrates of patients with SS. They tend to colocalize with salivary duct epithelial cells and acinar cells, and they potentially produce pro-inflammatory cytokines. Infiltrating lymphocytes with a CD69+CD103+/<sup>−</sup> tissue-resident phenotype and increased IFN-γ production were prominent in the submandibular glands of p40−/−CD25−/<sup>−</sup> mice used as a murine model of SS, indicating initiation of the inflammatory pathway. This knockout mitigated symptoms and reduced progression of the disease, elucidating the role of CD8a in SS [173]. Subsequently, genetic ablation of IFNγ resulted in decreased CD8<sup>+</sup> T cell infiltration and glandular tissue destruction. More importantly, depletion of CD8<sup>+</sup> T cells fully protected mice against the pathologic manifestations of SS, even after the onset of disease [173]. A subset of these CD8<sup>+</sup> T cells show an activated phenotype, as reflected in higher expression levels of HLA-DR where increased proportions of HLA-DR<sup>+</sup> T cells are associated with higher disease severity [174]. Increased HLA-DR expression has been observed in both CD4<sup>+</sup> and CD8<sup>+</sup> T cells in the blood of patients that were positive for anti-SSA antibodies. The frequencies of HLA-DR-expressing activated CD4<sup>+</sup> and CD8<sup>+</sup> T cells in blood correlated with high ESSDAI scores [174]. Whole blood transcriptomic studies, serum proteomics, and peripheral immunophenotyping show a proportion of activated CD8<sup>+</sup> T cells in blood that indicate an activated gene signature profile [175]. CXCR3 is necessary for the migration of CD8<sup>+</sup> T cells into SGs [176]. High ESSDAI scores correspond to the activation of CD8<sup>+</sup> T cells in lymphoid organs, CXCR3 upregulation, and consequent migration to the SGs [174]. Within the LGs and SGs of NOD mice, CD8 T cells proliferate, express an activated phenotype, and produced inflammatory cytokines. Transfer of purified CD8 T cells isolated from the cervical lymph nodes of NOD mice into NOD-severe combined immunodeficiency recipients resulted in inflammation of the LGs, but was not sufficient to cause inflammation of the SGs as observed in the study by Barr et al., demonstrating that CD8 T cells have a pathogenic role in LG autoimmunity [177].

Tissue auto-antigen responses and activated CD8<sup>+</sup> T cells have not been well characterized in explaining autoimmune diseases like SS. Identifying human leukocyte antigen class I (HLA-I) binding peptide motifs gives insight to CD8<sup>+</sup> T cells involved in pSS, but their role in pathogenicity and progression of the disease besides secretion of cytokines, primarily TNF-α, and IFN-γ is still unclear. New findings in the pathophysiology of CD8<sup>+</sup> T cells in autoimmunity and a better understanding of their activation may provide opportunities for the development of targeted immunologic therapies in various autoimmune disorders.
