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Sima Hirani, Ping Chen, Shayma Jawad, Ian Thompson, Baoying Liu, Lai Wei, H Nida Sen, Richard Lee, Robert Nussenblatt; Altered CD8+ T cell function in human non-infectious uveitis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2026.
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Although CD8+ T cells are primarily implicated in the clearance of viral infections, they have also recently been shown to be a key determinant of clinical prognosis in patients with non-ocular autoimmune diseases. This challenges the conventional paradigm of CD4+ T cell driven autoimmunity, and raises new questions about the role of CD8+ cells in non-infectious inflammation. We therefore interrogated the phenotype and function of CD8+ cells in patients with sight threatening autoimmune uveitis.
Fresh whole blood from uveitis patients (n=25) and healthy controls (HCs, n=25) was analyzed using flow cytometry. Three subsets of CD8+ cells were distinguished based on surface expression of CD45RA, CD28 and CCR7, representing naïve (CD28+CCR7+CD45RA+), effector memory (CD28+CCR7-CD45RA-), and late differentiated (CD28-CCR7-CD45RA+) cells. The cytotoxic potential of these subsets was then assessed by CD107a expression, and functional killing was quantified by determining the percentage of CFSE+Propidium Iodide+ cells after 6 hours of CD8+ cell co-culture with a CFSE labeled target K562 cell line. Intracellular expression of the transcription factor T-bet , which is a master regulator of CD8+ effector function, was also assessed by flow cytometry.
The proportions of all three CD8+ cell subsets were similar in both uveitis patients and HCs (CD28+CCR7+ ~25%, CD28+CCR7- ~33%, and CD28+CCR7+ ~25%). However, there was a significantly higher percentage of CD107a+ CD8+ cells in uveitis patients (p=0.03). CD8+ cells from uveitis patients also demonstrated a greater capacity to kill target cells (10% vs 3% in HCs) and, in addition, the percentage of cells expressing T-bet was significantly increased in effector memory CD8+ cells from uveitis patients (p<0.0001). A higher percentage of CD8+ cells from uveitis patients were TNF-α+ and IFN-γ+ (62% vs 43% in HCs) but a lower percentage of cells expressed IL-2 (13% vs 25% in HCs).
The increased expression of CD107a and T-bet in effector memory (CD28+CCR7-CD45RA-) CD8+ T cells from uveitis patients indicates a greater capacity for cytotoxicity and this is reflected in enhanced CD8+ T cell killing. This is the first report of altered CD8+ cell function in patients with sight-threatening non-infectious uveitis, and further investigations are now needed to determine whether this contributes to the pathogenesis of intraocular inflammation.
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