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Title: Cooperation of Pd-1 and LAG-3 contributes to T-cell exhaustion in anaplasma marginale-infected cattle

Author
item OKAGAWA, TOMOHIRO - Hokkaido University
item KONNAI, SATORU - Hokkaido University
item DERINGER, JAMES - Washington State University
item Ueti, Massaro
item Scoles, Glen
item MURATA, SHIRO - Hokkaido University
item OHASHI, KAZUHIKO - Hokkaido University
item BROWN, WENDY - Washington State University

Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/18/2016
Publication Date: 9/19/2016
Citation: Okagawa, T., Konnai, S., Deringer, J.R., Ueti, M.W., Scoles, G.A., Murata, S., Ohashi, K., Brown, W.C. 2016. Cooperation of Pd-1 and LAG-3 contributes to T-cell exhaustion in anaplasma marginale-infected cattle. Infection and Immunity. doi: 10.1128/IAI.00278-16.

Interpretive Summary: Cellular immune response such as CD4+ T-cell lymphocyte is central for control of Anaplasma marginale infection in cattle. However, infection of A. marginale suppress the immune response to antigen-specific CD4+ T cells in cattle immunized with Anaplasma proteins. In this study, we tested if T-cell exhaustion following infection is induced by the upregulation of immunoinhibitory receptors on T cells. T-cell responses and the kinetics of exhausted T cells in A. marginale-challenged cattle immunized with outer membrane (OM) proteins were monitored. Induction of T-cell exhaustion required the presence of the specific priming T-cell epitope on the infecting bacteria, suggesting T-cell receptor engagement by the immunization-primed T cells was involved. We show in this study that induction of T cell immunoinhibitory receptors programmed death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3) are upregulated on all T cell subsets following infection, with highest percentages of PD-1+ LAG-3+ double positive T cells occurring at the peak of infection, concurrent with the rapid loss of A. marginale-specific CD4 T cell responses. The results obtained here support the contribution of PD-1 and LAG-3 receptor-ligand interactions in inhibiting the A. marginale antigen induced-specific CD4 T-cell recall response following Anaplasma infection in cattle.

Technical Abstract: The CD4+ T-cell response is central for 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 (OM), which presumably facilitates 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+LAG-3+ exhausted T cells were monitored in A. marginale-challenged cattle previously immunized with OM. Consistent with previous studies, OM-specific proliferation of peripheral blood mononuclear cells (PBMCs) and interferon-' (IFN-') production were remarkably suppressed in the challenged animals by 5 weeks post-infection (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 ' T-cell populations gradually increased and also peaked at 5 wpi. A large increase in the percentage of LAG-3+ ' T cells was also observed. Importantly, in vitro blockade of the PD-1 and LAG-3 pathways partially restored OM-specific PBMC proliferation and IFN-' production at 5 wpi. These results indicate that the co-expression of PD-1 and LAG-3 on T cells contributes to rapid exhaustion of the T-cell response to A. marginale following infection and that PD-1 and LAG-3 are molecular targets that regulate T-cell response during bovine anaplasmosis.