Cooperation of PD-1 and LAG-3 contributes to T-cell exhaustion in Anaplasma marginale-infected cattle

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Abstract

The CD4+ T-cell response is central for the control of Anaplasma marginale infection in cattle. However, the infection induces a functional exhaustion of antigen-specific CD4+ T cells in cattle immunized with A. marginale outer membrane proteins or purified outer membranes (OMs), which presumably facilitates the persistence of this rickettsia. In the present study, we hypothesize that T-cell exhaustion following infection is induced by the upregulation of immunoinhibitory receptors on T cells, such as programmed death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3). OM-specific T-cell responses and the kinetics of PD-1-positive (PD-1+) LAG-3+ exhausted T cells were monitored in A. marginale-challenged cattle previously immunized with OMs. Consistent with data from previous studies, OM-specific proliferation of peripheral blood mononuclear cells (PBMCs) and interferon gamma (IFN-γ) production were significantly suppressed in challenged animals by 5 weeks postinfection (wpi). In addition, bacteremia and anemia also peaked in these animals at 5 wpi. Flow cytometric analysis revealed that the percentage of PD-1+ LAG-3+ T cells in the CD4+, CD8+, and γδ T-cell populations gradually increased and also peaked at 5 wpi. A large increase in the percentage of LAG-3+ γδ T cells was also observed. Importantly, in vitro, the combined blockade of the PD-1 and LAG-3 pathways partially restored OM-specific PBMC proliferation and IFN-γ production at 5 wpi. Taken together, these results indicate that coexpression of PD-1 and LAG-3 on T cells contributes to the rapid exhaustion of A. marginale-specific T cells following infection and that these immunoinhibitory receptors regulate T-cell responses during bovine anaplasmosis.

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Okagawa, T., Konnai, S., Deringer, J. R., Ueti, M. W., Scoles, G. A., Murata, S., … Brown, W. C. (2016). Cooperation of PD-1 and LAG-3 contributes to T-cell exhaustion in Anaplasma marginale-infected cattle. Infection and Immunity, 84(10), 2779–2790. https://doi.org/10.1128/IAI.00278-16

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