College of Agriculture & Natural Resources

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    Synergistic Activation of Bovine CD4+ T Cells by Neutrophils and IL-12
    (MDPI, 2021-06-03) Xiao, Zhengguo; Kandel, Anmol; Li, Lei
    CD4+ T cell activation requires inflammatory cytokines to provide a third signal (3SI), such as interleukin-12 (IL-12). We recently reported that bovine neutrophils can enhance the activation of bovine CD4+ T cells. To explore the interactions between neutrophils and third signal cytokines in bovine CD4+ T cell activation, naïve CD4+ T cells were isolated from cattle lymph nodes and stimulated for 3.5 days with anti-bovine CD3 (first signal; 1SI), anti-bovine CD28 (second signal; 2SI), and recombinant human IL-12 (3SI) in the presence or absence of neutrophils harvested from the same animals. Indeed, the strongest activation was achieved in the presence of all three signals, as demonstrated by CD25 upregulation, IFNγ production in CD4+ T cells, and secretion of IFNγ and IL-2 in cell supernatants. More importantly, 1SI plus neutrophils led to enhanced CD25 expression that was further increased by IL-12, suggesting synergistic action by IL-12 and neutrophils. Consistently, neutrophils significantly increased IFNγ production in 1SI plus IL-12-stimulated CD4+ T cells. Our data suggest the synergy of neutrophils and IL-12 as a novel regulator on bovine CD4+ T cell activation in addition to three signals. This knowledge could assist the development of immune interventions for the control of infectious diseases in cattle.
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    The role of interleukin-12 for mTOR regulation of memory CTLs
    (2014) Garcia, Karla; Xiao, Zhengguo; Animal Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    A major goal of vaccines is to induce functional immune memory, and efforts to improve the efficacy of vaccines targeting memory CTLs have revealed an important immunoregulatory role of rapamycin, a specific mTOR inhibitor. While inflammatory cytokines are critical for memory CTLs formation, it is unknown if cytokines such as IL-12 mediate rapamycin's regulation during infection. Inhibition of mTOR by rapamycin represses CTL expansion but enhances central memory during vaccinia virus infection in mice. Without IL-12, immunoregulatory effects of rapamycin on CTL expansion and subsequent memory formation are diminished, yet present compared to CTLs not treated with rapamycin. In infected mice, rapamycin directly enhances IL-12 signaling in WT CTLs by upregulating IL-12 receptor-B2 and STAT4 phosphorylation. Furthermore, secondary expansion of rapamycin-regulated memory CTLs in IL-12 receptor knockouts is impaired and resultant secondary memory CTLs are abolished. This indicates that interplay between cytokines and adjuvants should be considered during vaccine design.