Villinger Francois, Mayne Ann E, Bostik Pavel, Mori Kazuyasu, Jensen Peter E, Ahmed Rafi, Ansari Aftab A
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Virol. 2003 Jan;77(1):10-24. doi: 10.1128/jvi.77.1.10-24.2003.
By using the dominant simian immunodeficiency virus (SIV) Gag Mamu-A01 restricted major histocompatibility complex (MHC) class I epitope p11CM, we demonstrate antibody-mediated enhanced MHC class I cross presentation of SIV Gag. In vitro restimulation of peripheral blood mononuclear cells from SIV-infected rhesus macaques with recombinant full-length SIV Gag p55 plus p55 affinity-purified immunoglobulin G (p55 Gag/p55-IgG) led to the generation of markedly higher frequencies of p11CM specific precursor cytotoxic T lymphocytes (p-CTLs) compared with restimulation with (i) SIV Gag p55 alone or (ii) optimal concentrations of the p11CM peptide alone. These results, along with the finding that CD4 depletion abrogated the enhancement, suggest a prominent role for CD4(+) T cells. Testing for p-CTLs against other Mamu-A01-restricted SIV Gag epitopes suggested that this mechanism favored recognition of the dominant p11CM peptide, potentially further skewing of the CTL response. The p-CTL enhancing effect was also decreased or abrogated by pepsin digestion of the p55-specific IgG or by the addition of monoclonal antibodies to Fc receptor (FcR) II/III, suggesting that the effect was dependent on FcR-mediated uptake of the immune-complexed antigen. Finally, incubation of antigen-presenting cells with SIV Gag p55 immune complexes in the presence of lactacystin or of bafilomycin indicated that the mechanism of antibody-mediated enhancement of cross presentation required both the proteasomal and the endosomal pathways. These data demonstrate for the first time the cross presentation of antigens via immune complexes in lentiviral infection and indicate a heretofore-unrecognized role for antibodies in modulating the magnitude and potentially also the breadth of MHC class I-restricted antigen processing and presentation and CTL responses.
通过使用主要的猿猴免疫缺陷病毒（SIV）Gag Mamu - A01限制性主要组织相容性复合体（MHC）I类表位p11CM，我们证明了抗体介导的SIV Gag的MHC I类交叉提呈增强。用重组全长SIV Gag p55加p55亲和纯化的免疫球蛋白G（p55 Gag/p55 - IgG）对SIV感染的恒河猴外周血单核细胞进行体外再刺激，与用（i）单独的SIV Gag p55或（ii）单独的最佳浓度的p11CM肽进行再刺激相比，导致产生的p11CM特异性前体细胞毒性T淋巴细胞（p - CTL）频率显著更高。这些结果，连同CD4耗竭消除增强作用这一发现，表明CD4(+) T细胞起重要作用。针对其他Mamu - A01限制性SIV Gag表位的p - CTL检测表明，该机制有利于识别主要的p11CM肽，可能进一步使CTL反应发生偏差。p55特异性IgG经胃蛋白酶消化或添加针对Fc受体（FcR）II/III的单克隆抗体也会降低或消除p - CTL增强作用，这表明该作用依赖于FcR介导的免疫复合物抗原摄取。最后，在存在乳胞素或巴弗洛霉素的情况下，用SIV Gag p55免疫复合物孵育抗原呈递细胞表明，抗体介导的交叉提呈增强机制需要蛋白酶体和内体途径。这些数据首次证明了慢病毒感染中通过免疫复合物进行抗原交叉提呈，并表明抗体在调节MHC I类限制性抗原加工、提呈的幅度以及潜在的广度和CTL反应方面具有迄今未被认识的作用。
