Large granular lymphocytes are universally increased in human, macaque, and feline lentiviral infection

Abstract

Large granular lymphocytes (LGLs) have only been anecdotally reported in HIV infection. We previously reported an LGL lymphocytosis in FIV-infected cats associated with a rise in FIV proviral loads and a marked neutropenia that persisted during chronic infection. Extensive immunophenotyping of peripheral blood mononuclear cells in cats chronically infected with FIV were identified LGLs as CD8lo+FAS+; this cell population expanded commensurate with viral load. CD8lo+FAS+ cells expressed similar levels of interferon-γ compared to CD8lo+FAS+ cells from FIV-naive control animals, yet CD3ε expression, which was increased on total CD8+ T cells in FIV-infected cats, was decreased on CD8lo+FAS+ cells. Down-modulation of CD3 expression was reversed after culturing PBMC for 3 days in culture with ConA/IL-2. We identified CD8lo+FAS+ LGLs to be polyclonal T cells lacking CD56 expression. Blood smears from HIV-infected individuals and SIVmac239-infected rhesus macaques revealed increased LGLs compared to HIV/SIV negative counterparts. In humans, there was no correlation with viral load or treatment and in macaques the LGLs arose in acute SIV infection with increases in viremia. This is the first report describing and partially characterizing LGL lymphocytosis in association with lentiviral infections in three different species.

Applications of the FIV Model to Study HIV Pathogenesis

“…Large granular lymphocytes (LGLs) are a lymphoid subset comprising 10–15% of peripheral mononuclear blood cells (PBMCs) ( Figure 3 ), and consist of either CD3− NK cells or CD3+ T-cells that mediate antibody-dependent cytotoxicity [ 115 , 116 , 117 , 118 ]. Analysis of LGL populations during HIV infection have been hampered by the low percentage of these cells in circulation, and has typically only been reported in association with neoplasia [ 118 , 119 , 120 ]. However, recent studies have shown that LGLs are detectable and are elevated during HIV infection in humans, and may represent viral-suppressive CD8+ T cells [ 118 , 121 ].…”

“…Analysis of LGL populations during HIV infection have been hampered by the low percentage of these cells in circulation, and has typically only been reported in association with neoplasia [ 118 , 119 , 120 ]. However, recent studies have shown that LGLs are detectable and are elevated during HIV infection in humans, and may represent viral-suppressive CD8+ T cells [ 118 , 121 ]. Interestingly, studies in FIV-infected cats have determined that similar elevations in LGL phenotypes may represent polyclonal T-cells with viral suppressive properties, as indicated by increased interferon-γ (IFN-γ) expression and decreased PBMC proviral loads in correlation with LGL lymphocytosis [ 118 , 122 ].…”

Applications of the FIV Model to Study HIV Pathogenesis

“…The net effect of this event is a decrease in the ratio of CD4+ cells to CD8 + cells (CD4:CD8), and is used as a clinical indicator of immunosuppression in both FIV and HIV infected patients[108][109][110]. Additionally, several studies have shown that FIV induces defects in immune function similar to HIV, such as a decreased proliferation response of T lymphocytes in response to mitogens, a deficit in the humoral immune response, and dysregulation of cytokine expression[10,24,59].Large granular lymphocytes (LGLs) are a lymphoid subset comprising 10-15% of peripheral mononuclear blood cells (PBMCs)(Figure 3), and consist of either CD3-NK cells or CD3+ T-cells that mediate antibody-dependent cytotoxicity[111][112][113][114]. Analysis of LGL populations during HIV infection have been hampered by the low percentage of these cells in circulation, and has typically only been reported in association with neoplasia[114][115][116].…”

“…Additionally, several studies have shown that FIV induces defects in immune function similar to HIV, such as a decreased proliferation response of T lymphocytes in response to mitogens, a deficit in the humoral immune response, and dysregulation of cytokine expression[10,24,59].Large granular lymphocytes (LGLs) are a lymphoid subset comprising 10-15% of peripheral mononuclear blood cells (PBMCs)(Figure 3), and consist of either CD3-NK cells or CD3+ T-cells that mediate antibody-dependent cytotoxicity[111][112][113][114]. Analysis of LGL populations during HIV infection have been hampered by the low percentage of these cells in circulation, and has typically only been reported in association with neoplasia[114][115][116]. However, recent studies have shown thatLGLs are detectable and elevated during HIV infection in humans, and may represent viralsuppressive CD8+ T cells[114,117].…”

“…Analysis of LGL populations during HIV infection have been hampered by the low percentage of these cells in circulation, and has typically only been reported in association with neoplasia[114][115][116]. However, recent studies have shown thatLGLs are detectable and elevated during HIV infection in humans, and may represent viralsuppressive CD8+ T cells[114,117]. Interestingly, studies in FIV-infected cats have determined that similar elevations in LGL phenotypes may represent polyclonal T-cells with viral suppressive properties, indicated by increased interferon- (IFN-) expression and decreased PBMC proviral loads in correlation with LGL lymphocytosis[114,118].…”