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The CD4+ T-cell response is central for the control ofAnaplasma marginale infection in cattle. However, the infection induces a functional exhaustion of antigen-specific CD4+ T cells in cattle immunized withA. 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 inA. 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 ofA. marginale -specific T cells following infection and that these immunoinhibitory receptors regulate T-cell responses during bovine anaplasmosis.

Cooperation of PD-1 and LAG-3 Contributes to T-Cell Exhaustion in Anaplasma marginale-Infected Cattle