Cross Priming

Toward a Molecular Explanation for Cross-presentation of Antigens to the Immune System
Bernard Khor and Robert S. Makar
Cross-presentation is increasingly recognized as a key mechanism by which specific antigen-presenting cells (APCs) activate the cellular immune system against virally infected or neoplastic cells. These APCs have the capacity to acquire exogenous proteins by phagocytosis orendocytosis, derive antigenic peptides, and then crosspresent them in the context of class I major histocompatibility complex molecules. Because APCs provide both an antigenic stimulus and costimulatory signals, they can effectively activate naive CD8+ T lymphocytes, resulting in a brisk cellular immune response. The precise cellular pathways that permit an exogenous antigen to be presented in thecontext of class I major histocompatibility complex is the focus of intense investigation that has illuminated our understanding of the cell biology of APCs. This article reviews our understanding of how APCs cross-present antigen, illustrating how this process differs from the canonical pathways of antigen presentation. We define the central players required for crosspresentation and then focus onrecent studies that reveal the molecular mechanisms underlying this phenomenon. Understanding these mechanisms will likely inform the development of effective cell-based vaccines and other cellular immunotherapies and is therefore of interest to practitioners of transfusion medicine. C 2008 Elsevier Inc. All rights reserved.

ELLULAR immunotherapies represent an exciting emerging technology intransfusion medicine. Donor leukocyte infusion is now recognized as an effective therapy for relapse of chronic myelogenous leukemia after allogeneic hematopoietic progenitor cell transplant.1-4 Tumor-specific cellular vaccines resulting from ex vivo manipulation of antigen-presenting cells (APCs)5 and cancer cells6 may provide an effective, tailored therapy for cancer patients. In addition,dendritic cell (DC)– based vaccines may provide an effective therapy for chronic HIV-1 infection.7 A common goal underlying many of these interventions is to generate or augment a potent CD8+ T-lymphocyte response that will eradicate an invading tumor or virus. Although neoplastic and virally infected tissues may express the appropriate class I major histocompatibility complex (MHC)–peptide complexesnecessary for targeted destruction by mature, activated CD8+ T lymphocytes, they lack the requisite costimulatory molecules to activate naive CD8+ T lymphocytes and thus initiate the cellular immune response. Therefore, understanding the precise mechanisms by which naive CD8+ T lymphocytes are activated in vivo will likely facilitate the development of more

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effective immunotherapies.Cross-presentation is now understood to be an important mechanism that APCs use to prime the cellular immune system against foreign antigens.
CANONICAL PATHWAYS FOR ANTIGEN PRESENTATION

From the Department of Pathology, Blood Transfusion Service, Massachusetts General Hospital, Boston, MA. Address reprint requests to Robert S. Makar, Blood Transfusion Service, 55 Fruit St, GRJ2-206C Boston, MA.E-mail: rmakar@partners.org 0887-7963/08/$ - see front matter n 2008 Elsevier Inc. All rights reserved. doi: 10.1016/j.tmrv.2008.02.002

T lymphocytes are central players in the adaptive immune system. Through the elaboration of cytokines, CD4+ (helper) T lymphocytes regulate the activation of macrophages, the proliferation and differentiation of B-lymphocytes, and the activation of CD8+ (cytotoxic)T lymphocytes (CTL). Activated CD8+ T lymphocytes, in turn, mediate cytolysis of host cells infected with intracellular microbes by inducing apoptosis in their targets. 8 Antigen-presenting cells are required to efficiently stimulate both CD4+ and CD8+ T-lymphocyte responses. Many different kinds of immune cells function as APCs, including B cells, macrophages, and DCs, but DCs are the most...