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Rapid Deletion of Antigen-Specific CD4⁺ T Cells following Infection Represents a Strategy of Immune Evasion and Persistence for Anaplasma marginale¹

Sushan Han^2,*, Junzo Norimine^2,*, Guy H. Palmer^*, Waithaka Mwangi, Kevin K. Lahmers^* and Wendy C. Brown^3,*

^* Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164; and Department of Veterinary Pathobiology, Texas A & M University, College Station, TX 77843

Acquired T cell immunity is central for protection against infection. However, the immunological consequences of exposing memory T cells to high Ag loads during acute and persistent infection with systemic pathogens are poorly understood. We investigated this by using infection with Anaplasma marginale, a ruminant pathogen that replicates to levels of 10⁹ bacteria per ml of blood during acute infection and maintains mean bacteremia levels of 10⁶ per ml during long-term persistent infection. We established that immunization-induced Ag-specific peripheral blood CD4⁺ T cell responses were rapidly and permanently lost following infection. To determine whether these T cells were anergic, sequestered in the spleen, or physically deleted from peripheral blood, CD4⁺ T lymphocytes from the peripheral blood specific for the major surface protein (MSP) 1a T cell epitope were enumerated by DRB3*1101 tetramer staining and FACS analysis throughout the course of immunization and challenge. Immunization induced significant epitope-specific T lymphocyte responses that rapidly declined near peak bacteremia to background levels. Concomitantly, the mean frequency of tetramer⁺CD4⁺ cells decreased rapidly from 0.025% before challenge to a preimmunization level of 0.0003% of CD4⁺ T cells. Low frequencies of tetramer⁺CD4⁺ T cells in spleen, liver, and inguinal lymph nodes sampled 9–12 wk postchallenge were consistent with undetectable or unsustainable Ag-specific responses and the lack of T cell sequestration. Thus, infection of cattle with A. marginale leads to the rapid loss of Ag-specific T cells and immunologic memory, which may be a strategy for this pathogen to modulate the immune response and persist.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01-AI053692 and R01-AI44005.

² S.H. and J.N. contributed equally to this paper.

³ Address correspondence and reprint requests to Dr. Wendy C. Brown, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164. E-mail address: wbrown{at}vetmed.wsu.edu

⁴ Abbreviations used in this paper: MSP, major surface protein; BCG, Bacille Calmette-Guérin; LN, lymph node; RAP-1, rhoptry-associated protein 1; URBC, uninfected erythrocyte membrane.