Trogocytosis of MHC-I/Peptide Complexes Derived from Tumors and Infected Cells Enhances Dendritic Cell Cross- Priming and Promotes Adaptive T Cell Responses Qian-Jin Zhang 1 *, Xiao-Lin Li 1 , David Wang 1 , Xiao-Cong Huang 1 , J. Michael Mathis 1 , Wei-Ming Duan 1 , David Knight 1 , Runhua Shi 1 , Jonathan Glass 1 , Dong-Qing Zhang 2 , Lea Eisenbach 3 , Wilfred A. Jefferies 4 1 Department of Cellular Biology and Anatomy, Gene Therapy Program, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana, United States of America, 2 Medical School of Shanghai Jiao Tong University, Shanghai, China, 3 Department of Immunology, Weizmann Institute of Science, Rehovot, Israel, 4 The Michael Smith Laboratories and the Biomedical Research Centre, Departments of Medical Genetics, Microbiology and Immunology and Zoology, University of British Columbia, Vancouver, British Columbia, Canada Abstract The transporter associated with antigen processing (TAP) and the major histocompatibility complex class I (MHC-I), two important components of the MHC-I antigen presentation pathway, are often deficient in tumor cells. The restoration of their expression has been shown to restore the antigenicity and immunogenicity of tumor cells. However, it is unclear whether TAP and MHC-I expression in tumor cells can affect the induction phase of the T cell response. To address this issue, we expressed viral antigens in tumors that are either deficient or proficient in TAP and MHC-I expression. The relative efficiency of direct immunization or immunization through cross-presentation in promoting adaptive T cell responses was compared. The results demonstrated that stimulation of animals with TAP and MHC-I proficient tumor cells generated antigen specific T cells with greater killing activities than those of TAP and MHC-I deficient tumor cells. This discrepancy was traced to differences in the ability of dendritic cells (DCs) to access and sample different antigen reservoirs in TAP and MHC-I proficient versus deficient cells and thereby stimulate adaptive immune responses through the process of cross- presentation. In addition, our data suggest that the increased activity of T cells is caused by the enhanced DC uptake and utilization of MHC-I/peptide complexes from the proficient cells as an additional source of processed antigen. Furthermore, we demonstrate that immune-escape and metastasis are promoted in the absence of this DC ‘arming’ mechanism. Physiologically, this novel form of DC antigen sampling resembles trogocytosis, and acts to enhance T cell priming and increase the efficacy of adaptive immune responses against tumors and infectious pathogens. Citation: Zhang Q-J, Li X-L, Wang D, Huang X-C, Mathis JM, et al. (2008) Trogocytosis of MHC-I/Peptide Complexes Derived from Tumors and Infected Cells Enhances Dendritic Cell Cross-Priming and Promotes Adaptive T Cell Responses. PLoS ONE 3(8): e3097. doi:10.1371/journal.pone.0003097 Editor: Aric Gregson, University of California Los Angeles, United States of America Received April 22, 2008; Accepted August 4, 2008; Published August 29, 2008 Copyright: ß 2008 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by Louisiana Board of Regents, Feist-Weiller Cancer Center, Louisiana State Gene Therapy Program and Department of Cellular Biology & Anatomy at LSU Health Sciences Center-Shreveport. Dr. Dong-Qing Zhang is supported by National Natural Science Foundation of China (No., No.), Shanghai Commission of Science and Technology (No. 07JC14033) and Shanghai Leading Academic Discipline Project (T0206). Dr. Wilfred A. Jefferies is supported by CIHR and PCRF. Competing Interests: The authors have declared that no competing interests exist. * E-mail: qzhang@lsuhsc.edu Introduction Adaptive T cell immune responses play a critical role in controlling and destroying tumor cells. However, tumors that are deficient in components of the MHC-I antigen presentation pathway, such as TAP and MHC-I, are often observed to escape T cell responses [1–5]. This is due to failure in presentation of tumor antigens on the cell surface when TAP and MHC-I are absent [2– 5]. TAP functions to transport cytosolic-generated peptides into the lumen of the endoplasmic reticulum (ER) for MHC-I binding, followed by transport of MHC-I/peptide complexes to the cell surface for T cell recognition. Restoration of TAP and MHC-I expression in tumor cells has been demonstrated to increase T cell-based tumor antigen-specific immune responses [6–11]. Such responses consist of two phases, the induction and effector phases. The induction phase occurs in the early stages of the T cell immunity, initiating tumor-antigen recognition and antigen specific T cell generation and prolifera- tion, while the effector phase occurs in later stages of the immune response, affecting T cell activation, recognition and destruction of antigen-expressing tumor cells. Using existing antigen specific T cells, many reports have confirmed that increased TAP and MHC-I expression in tumor cells restores the capacity for antigen presentation and thus enhances recognition and destruction of tumor cells by antigen specific T cells [10,12–14]. These reports provide evidence that TAP and MHC-I expression facilitates T cell immunity in the effector phase. In addition to these, there are several studies indicating that restoration of TAP and MHC-I expression in tumor cells can augment T cell-based anti-tumor immune responses in both the induction and effector phases, by augmenting tumor immunogenicity. In these studies, tumor immunogenicity augmented by TAP and/or MHC-I expression was measured using tumor-cell-induced T cell responses to monitor the capacity for antigen processing and presentation of the tumor [10,14] or through the use of tumor-bearing mice as a model to determine the length of survival as a quotient for PLoS ONE | www.plosone.org 1 August 2008 | Volume 3 | Issue 8 | e3097