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Title: Loss of immunization-induced epitope-specific CD4 T-cell response following anaplasma marginale infection requires presence of the T-cell epitope on the pathogen and is not associated with an increase in lymphocytes

item BROWN, WENDY - Washington State University
item TURSE, JOSHUA - Washington State University
item LAWRENCE, PAULRAJ - Washington State University
item Johnson, Wendell
item Scoles, Glen
item DERINGER, JAMES - Washington State University
item SUTTEN, ERIC - Washington State University
item HAN, SUSHAN - Washington State University
item NORIMINE, JUNZO - Washington State University

Submitted to: Clinical and Vaccine Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2015
Publication Date: 4/29/2015
Citation: Brown, W.C., Turse, J.E., Lawrence, P.K., Johnson, W.C., Scoles, G.A., Deringer, J.R., Sutten, E.L., Han, S., Norimine, J. 2015. Loss of immunization-induced epitope-specific CD4 T-cell response following anaplasma marginale infection requires presence of the T-cell epitope on the pathogen and is not associated with an increase in lymphocytes. Clinical and Vaccine Immunology. 22(7):742-53.

Interpretive Summary: Anaplasma marginale is a tick-borne intraerythrocytic rickettsial pathogen found in most temperate and tropical regions of the world and causes significant anemia and a mortality rate of up to 30% in naive cattle. Cattle that survive acute disease remain persistently infected for life with cyclic, but microscopically undetectable, levels of bacteremia that do not cause clinical disease. Methods to prevent disease rely on antibiotic and acaricide treatment, which are expensive, difficult to administer in extensive rearing conditions, and only partially effective. Thus, we are working toward understanding the bovine immune response to infection into order to develop an effective vaccine. Our studies have shown that infection of A. marginale in cattle that have been previously immunized with candidate vaccines have a complete loss of functional CD4 T-cell responses, indicating that the presence of the pathogen specifically suppresses the immune response directed toward the pathogen. The data reported in this paper extend those findings and indicate that the loss of the immune response is not due to the presence of regulatory T cells.

Technical Abstract: We have shown that in cattle previously immunized with outer membrane proteins, infection with Anaplasma marginale induces a functionally exhausted CD4 T-cell response to the A. marginale immunogen. Furthermore, T-cell responses following infection in nonimmunized cattle had a delayed onset and were sporadic and transient during persistent infection. The induction of an exhausted T-cell response following infection presumably facilitates pathogen persistence. In the current study, we hypothesized that the loss of epitope-specific T-cell responses requires the presence of the immunizing epitope on the pathogen, and T-cell dysfunction correlates with the appearance of regulatory T cells. In limited studies in cattle, regulatory T cells have been shown to belong to T-cell subsets rather than be CD4 T cells expressing forkhead box protein P3 (FoxP3). Cattle expressing the DRB3*1101 haplotype were immunized with a truncated A. marginale major surface protein (MSP) 1a that contains a DRB3*1101-restricted CD4 T-cell epitope, F2-5B. Cattle either remained unchallenged or were challenged with A. marginale bacteria that express the epitope or with A. marginale subsp. centrale that do not. Peripheral blood and spleen mononuclear cells were monitored for MSP1a epitope F2-5B-specfic T-cell proliferative responses and were stained for T-cell subsets or CD4+ CD25+ FoxP3+ Tcells before and during infection. As hypothesized, the induction of T-cell exhaustion occurred only following infection with A. marginale, which did not correlate with an increase in either CD4+ CD25+ FoxP3+ T cells or any gamma delta T-cell subset examined.