Han Sushan, Norimine Junzo, Palmer Guy H, Mwangi Waithaka, Lahmers Kevin K, Brown Wendy C
Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164, USA.
J Immunol. 2008 Dec 1;181(11):7759-69. doi: 10.4049/jimmunol.181.11.7759.
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 10(9) bacteria per ml of blood during acute infection and maintains mean bacteremia levels of 10(6) 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.
获得性T细胞免疫对于预防感染至关重要。然而，在全身性病原体的急性和持续性感染期间，使记忆T细胞暴露于高抗原负荷下的免疫后果却知之甚少。我们通过使用边缘无形体感染来研究这一问题，边缘无形体是一种反刍动物病原体，在急性感染期间可复制至每毫升血液中有10⁹个细菌，在长期持续性感染期间维持每毫升10⁶个的平均菌血症水平。我们发现，感染后免疫诱导的抗原特异性外周血CD4⁺ T细胞反应迅速且永久性丧失。为了确定这些T细胞是无反应性的、被隔离在脾脏中还是从外周血中被物理清除，在免疫和攻击的整个过程中，通过DRB3*1101四聚体染色和流式细胞术分析对外周血中针对主要表面蛋白（MSP）1a T细胞表位的CD4⁺ T淋巴细胞进行计数。免疫诱导了显著的表位特异性T淋巴细胞反应，这些反应在菌血症峰值附近迅速下降至背景水平。与此同时，四聚体⁺CD4⁺细胞的平均频率从攻击前的0.025%迅速降至免疫前CD4⁺ T细胞的0.0003%水平。在攻击后9 - 12周采集的脾脏、肝脏和腹股沟淋巴结中，四聚体⁺CD4⁺ T细胞频率较低，这与无法检测到或无法维持的抗原特异性反应以及缺乏T细胞隔离一致。因此，牛感染边缘无形体导致抗原特异性T细胞和免疫记忆迅速丧失，这可能是该病原体调节免疫反应并持续存在的一种策略。
