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To evaluate changes in the phenotypic heterogeneity and function of CD8 T cells in the intestinal epithelium during primary SIV infection.Previous studies have shown an increased prevalence of CD8 T cells in the intestinal epithelium in HIV and SIV infections. As intestinal CD8 T cells are a heterogeneous population we evaluated their phenotypic distribution (CD8αβ, CD8αα) and function [interferon (IFN)-γ production] during primary SIV infection.The phenotype and functional potential of CD8 intestinal intraepithelial lymphocytes (IEL) prior to and following SIV infection were determined using flow cytometry.IEL were found to harbor CD8αβCD3, CD8ααCD3 and CD8αα+CD3− T-cell subsets. Most of the CD8CD4 double positive IEL expressed CD8αα homodimers. In primary SIV infection the frequency of CD8αβCD3 T cells increased dramatically whereas the frequency of CD8αα T cells declined. A higher frequency of CD8αβKi-67 IEL was observed following SIV infection suggesting that local cell proliferation might have contributed to an increased prevalence of CD8αβ IEL. In contrast, a severe depletion of CD8ααCD4 IEL occurred which contributed to the depletion of CD8αα IEL. The CD8αβ IEL were the major producers of IFN-γ in the intestinal epithelium and the frequency of IFN-γ-producing CD8αβ IEL was enhanced considerably in primary infection.CD8αβ IEL may be important in generating early antiviral responses at the intestinal epithelium. However, alterations in CD8 T-cell subsets and their function may reflect early immunopathogenic events in the intestinal mucosa.