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Title: Anaplasma marginale infection with persistent high-load bacteremia induces a dysfunctional memory CD4+ T lymphocyte response but sustained high IgG titers

Author
item HAN, SUSHAN - Washington State University
item NORIMINE, JUNZO - Washington State University
item BRAYTON, KELLY - Washington State University
item PALMER, GUY - Washington State University
item Scoles, Glen
item BROWN, WENDY - Washington State University

Submitted to: Clinical and Vaccine Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/30/2010
Publication Date: 12/20/2011
Citation: Han, S., Norimine, J., Brayton, K.A., Palmer, G.H., Scoles, G.A., Brown, W.C. 2011. Anaplasma marginale infection with persistent high-load bacteremia induces a dysfunctional memory CD4+ T lymphocyte response but sustained high IgG titers. Clinical and Vaccine Immunology. 17(12): 1881-1890. (doi:10.1128/CVI.00257-10).

Interpretive Summary: Control of blood-borne infections is dependent on antigen-specific effector and memory T cells and high affinity IgG responses. In chronic infections characterized by high antigen load, it has been shown that antigen-specific T and B cells are vulnerable to down-regulation and apoptosis. Anaplasma marginale is a persistent infection of cattle characterized by acute and chronic high-load bacteremia. We previously showed that CD4+ T cells primed by immunization with an A. marginale outer membrane proteins were rapidly deleted following infection. Furthermore, peripheral blood T cell responses to bacteria were not observed after acute infection was controlled. The current study more closely investigated the kinetics of A. marginale-specific CD4+ T cell responses primed during infection. Antigen-specific CD4+ T cell responses were first detected at five to seven weeks, but responses were sporadic and transient thereafter. By two weeks of infection cattle had developed high titers of A. marginale-specific IgG, which remained high throughout persistent infection. This dysfunctional CD4+ T cell response to infection is consistent with continual down regulation or deletion of newly primed effector T cells, similar to what was observed for immunization-induced T cells following A. marginale infection. The failure to establish a strong memory T cell response during A. marginale infection likely contributes to bacterial persistence.

Technical Abstract: Control of blood-borne infections is dependent on antigen-specific effector and memory T cells and high-affinity IgG responses. In chronic infections characterized by a high antigen load, it has been shown that antigen-specific T and B cells are vulnerable to downregulation and apoptosis. Anaplasma marginale is a persistent infection of cattle characterized by acute and chronic high-load bacteremia. We previously showed that CD4+ T cells primed by immunization with an A. marginale outer membrane protein were rapidly deleted following infection. Furthermore, peripheral blood T cell responses to bacteria were not observed after acute infection was controlled, suggesting dysfunctional T cell priming to other A. marginale antigens. The current study more closely investigated the kinetics of A. marginale-specific CD4+ T cell responses primed during infection. Frequent sampling of peripheral blood and spleens revealed that antigen-specific CD4+ T cell responses were first detected at 5 to 7 weeks, but the responses were sporadic and transient thereafter. A similar pattern was observed in animals sampled weekly for nearly 1 year. Paradoxically, by 2 weeks of infection, cattle had developed high titers of A. marginale-specific IgG, which remained high throughout persistent infection. This dysfunctional CD4+ T cell response to infection is consistent with continual downregulation or deletion of newly primed effector T cells, similar to what was observed for immunization-induced T cells following A. marginale infection. The failure to establish a strong memory T cell response during A. marginale infection likely contributes to bacterial persistence.