CCL5 Release by CCR9+ CD8 T Cells: A Potential Contributor to Immunopathology of Primary Sjögren’s Syndrome

Abstract

IntroductionIncreased CCL5 expression and CD8 T cells have been shown to be pivotal regulators of immunopathology in primary Sjögren’s syndrome (pSS) and pSS-like disease. Increased CCL5 expression by CCR9+ CD4 T cells has previously been implicated as a contributor to immunopathology in pSS. The role of CD8 T cells and in particular CCR9+ CD8 T cells and their potential to secrete CCL5 has not previously been studied in pSS. In this study we investigated both CCR9 and CCL5 expression by CD8 T cells in pSS patients compared to healthy controls (HC).MethodsCCR9 expression on CD8 T cells from peripheral blood was compared between patients with pSS and HC by flow cytometry. Intracellular CCL5 expression by naive, memory and effector CCR9- and CCR9+ CD8 T cells was assessed. In addition, the capacity and pace of CCL5 release upon T cell activation was determined for all subsets and compared with CD4 T cells.ResultsThe frequency of circulating CCR9+ CD8 T cells in pSS patients is increased compared to HC. Antigen-experienced CD8 T cells, especially CCR9+ effector CD8 T cells, express the highest CCL5 levels, and release the highest levels of CCL5 upon activation. Memory and effector CD8 T cells of pSS patients express significantly less CCL5 and subsequently release less CCL5 upon stimulation compared to HC. CCR9+ CD8 T cells rapidly release CCL5 and significantly more than CCR9+ CD4 T cells.ConclusionCCR9+ CD8 T cells express more CCL5 than CCR9- CD8 T cells. CCL5 is rapidly released upon activation, resulting in reduced intracellular expression. Reduced CCL5 expression by an elevated number of antigen-experienced CCR9-expressing CD8 T cells in pSS patients points towards increased release in vivo. This suggests that CCL5 release by CCR9+ CD8 T cells contributes to immunopathology in pSS.

In patients with primary Sjögren’s syndrome innate-like MAIT cells display upregulated IL-7R, IFN-γ, and IL-21 expression and have increased proportions of CCR9 and CXCR5-expressing cells

“…Earlier work from our group and others has shown increased CCR9 expression on CD4 and CD8 T cells in pSS compared to HC ( 21 – 24 ). In this study we confirmed these findings (representative dot plots in Figure 2A ).…”

“…Currently, it is unclear to what extent CD8 T cells and CD8 MAIT cells contribute to immune activation in pSS patients. Nonetheless, it was observed that CD8 T cells were found to associate with lymphocyte aggregates and Tfh numbers in salivary glands of pSS patients ( 24 ). Hence, we anticipate that increased CD8 MAIT cells may also significantly contribute to immune activation in the glandular lymphocytic foci given their effector profile.…”

“…The number of CCR9+ Tfh-like cells is elevated in peripheral blood of pSS patients. In (mucosa-associated) salivary glands of pSS patients both CCR9+ T cell numbers, and levels of its ligand CCL25 are elevated ( 21 – 24 ). In secretomes of salivary gland tissue CCL25 levels were also found to be associated with SSA positivity, B cell hyperactivity (serum IgG levels), and levels of IL-21 and soluble IL-7R ( 25 ).…”

The causal effects of circulating cytokines on sepsis: a Mendelian randomization study

“…RANTES, also known as CCL5, is a chemotactic cytokine, recruiting leukocytes to the site of inflammation ( Appay & Rowland-Jones, 2001 ). The chemokine CCL5 is mainly expressed by T-cells and monocytes and is abundantly expressed by epithelial cells, fibroblasts, and thrombocytes ( Hinrichs et al, 2022 ). One study found that low levels of RANTES are associated with mortality in children with cerebral malaria ( John et al, 2006 ), suggesting that RANTES has a positive role in counteracting infection.…”