Abstract
Granzyme B-expressing (GrB+) B cells are thought to contribute to immune dysfunctions in HIV patients, but so far their exact role is unknown. This report demonstrates for the first time the existence of GrB+ B cells in SIV-infected rhesus macaques, which represent the most commonly used nonhuman primate model for HIV research. Similar to HIV patients, we found significantly higher frequencies of these cells in the blood of chronically SIV-infected rhesus monkeys compared with uninfected healthy ones. These frequencies correlated with plasma viral load and inversely with absolute CD4 T-cell counts. When investigating GrB+ B cells in different compartments, levels were highest in blood, spleen and bone marrow, but considerably lower in lymph nodes and tonsils. Analysis of expression of various surface markers on this particular B-cell subset in SIV-infected macaques revealed differences between the phenotype in macaques and in humans. GrB+ B cells in SIV-infected rhesus macaques exhibit an elevated expression of CD5, CD10, CD25 and CD27, while expression of CD19, CD185 and HLA-DR is reduced. In contrast to human GrB+ B cells, we did not observe a significantly increased expression of CD43 and CD86. B-cell receptor stimulation in combination with IL-21 of purified B cells from healthy animals led to the induction of GrB expression. Furthermore, initial functional analyses indicated a regulatory role on T-cell proliferation. Overall, our data pave the way for longitudinal analyses including studies on the functionality of GrB+ B cells in the nonhuman primate model for AIDS.
Highlights
Human immunodeficiency virus infection results in a significant dysregulation of T, B and dendritic cells.1 Recently, a rare subset ofB cells producing IL(Interleukin)-10, called B-regulatory cells (Bregs), was identified in mice and humans.2 These Bregs were demonstrated to produce the serine protease granzyme B (GrB), GrB usually represents a major key component of natural killer cells and cytotoxic T lymphocytes.2,3 The existence ofB-cell-derived granzyme B has been described in the context of infectious or autoimmune diseases, for example, systemic lupus erythematosus,2 Sjogrens syndrome2,3 and EBV-induced mononucleosis.2 So far, the immunological function of these granzyme B-expressing (GrB+) B cells remains elusive, and may range from antiviral, cytotoxic to autoregulatory and regulatory functions.2,3 in a recent study, large numbers of circulating GrB+
Granzyme B-expressing (GrB+) B cells are thought to contribute to immune dysfunctions in HIV patients, but so far their exact role is unknown
We observed significantly higher frequencies of GrB+ B cells in blood of SIVmac251-infected animals 1 year post infection compared with healthy controls (SIV−: 1.17 ± 1.02%; simian immunodeficiency virus (SIV)+: 4.56 ± 3.69%; Figure 1b)
Summary
Granzyme B-expressing (GrB+) B cells are thought to contribute to immune dysfunctions in HIV patients, but so far their exact role is unknown. This report demonstrates for the first time the existence of GrB+ B cells in SIV-infected rhesus macaques, which represent the most commonly used nonhuman primate model for HIV research. Similar to HIV patients, we found significantly higher frequencies of these cells in the blood of chronically SIV-infected rhesus monkeys compared with uninfected healthy ones. These frequencies correlated with plasma viral load and inversely with absolute CD4 T-cell counts. Our data pave the way for longitudinal analyses including studies on the functionality of GrB+ B cells in the nonhuman primate model for AIDS. Immunology and Cell Biology (2017) 95, 316–320; doi:10.1038/icb.2016.96; published online 25 October 2016
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