Generation Of Cellmediated Immune Responses

The design of successful immunologic strategies to treat human virus-associated malignancies requires an understanding of the effector processes that control viral infection and the mechanisms viruses use to evade such responses. Immune responses against viruses are mediated by nonspecific effector cells, such as natural killers and macrophages, and antigen-specific T- and B-lymphocytes.

Antibody-mediated humoral immunity effectively neutralizes extracellular virus. Once inside the cell, viruses are likely to be protected from antibody and therefore

Cytokine Network

Fig. 1. Generation of cell-mediated immune response. For activation of naive T-helper (Th) and cytotoxic T-lymphocytes (CTLs), professional antigen-presenting cells (e.g., dendritic cells [DCs]) are required. DCs process the antigens and present the immunogenic peptides in an MHC context with simultaneous delivery of costimulatory signals (e.g., B7/CD28 or CD40/CD40 ligand signals) to activate T-lymphocytes. Two antigen-processing pathways are generally accepted. In the cytosolic pathway, endogenously synthesized antigens (cytoplasmic proteins) are digested in proteosomes and transported into the endoplasmic reticulum (ER) by transporters associated with antigen processing (TAPs), where they complex with MHC class I molecules for presentation to CD8+ CTLs. In the endosomal pathway, extracellular antigens are phagocytozed, digested in lysosomes, and then complexed with MHC class II molecules in vesicles for presentation to CD4+ Th-lymphocytes. See the text for more details.

Fig. 1. Generation of cell-mediated immune response. For activation of naive T-helper (Th) and cytotoxic T-lymphocytes (CTLs), professional antigen-presenting cells (e.g., dendritic cells [DCs]) are required. DCs process the antigens and present the immunogenic peptides in an MHC context with simultaneous delivery of costimulatory signals (e.g., B7/CD28 or CD40/CD40 ligand signals) to activate T-lymphocytes. Two antigen-processing pathways are generally accepted. In the cytosolic pathway, endogenously synthesized antigens (cytoplasmic proteins) are digested in proteosomes and transported into the endoplasmic reticulum (ER) by transporters associated with antigen processing (TAPs), where they complex with MHC class I molecules for presentation to CD8+ CTLs. In the endosomal pathway, extracellular antigens are phagocytozed, digested in lysosomes, and then complexed with MHC class II molecules in vesicles for presentation to CD4+ Th-lymphocytes. See the text for more details.

become the targets of cellular immune responses, usually resulting in eradication of the infected cell by CTLs. Professional antigen-presenting cells (i.e., dendritic cells [DCs] or macrophages) and T-helper lymphocytes orchestrate the CTL response (Fig. 1).

Virus-specific CD4+ T-helper (Th) lymphocytes and CD8+ CTLs generally mediate the effector mechanisms necessary and sufficient to resolve acute infection as well as provide recall immune responses to resist reexposure to acute viruses and to control the reactivation of latent viruses. Viruses have diverse mechanisms to evade immune responses (3), although in most cases the immune system prevails and controls the infection.

CD8 + CTLs recognize virus-infected cells through interaction of their T-cell receptor with peptides bound to the major histocompatibility complex (MHC) class I molecule of the infected cell. Endogenously synthesized proteins of the virus are degraded into short peptides by the antigen-processing machinery and presented in the MHC class I context (4). Peptides are generally 8-10 amino acids long, are generated within cells by a cytoplasmic proteolytic complex known as the proteosome, and are then transported into the endoplasmic reticulum by transporters associated with antigen processing (TAPs), where they are complexed with MHC class I molecules for cell surface presentation (5). Virtually all nucleated cells are MHC class I-positive and thus can be recognized when they are infected by a virus. For activating (priming) naive CTL precursors, the peptides must be presented by professional antigen-presenting cells (APCs), which can also provide the necessary costimulatory signals (i.e., interaction of B7 with CD28 or CD40 with CD40L on APC and T-cells, respectively) (6). If the T-cell receptor is engaged without costimulatory signals, T-lymphocytes can become anergized. Activated CTLs do not need the costimulatory molecules to exert their effector functions, namely, cytolysis or induction of apoptosis of the target cell.

CD4+ Th-lymphocytes recognize exogenous antigens that are phagocytosed, processed, and presented in the context of MHC class II. Only APCs that are MHC class II-positive can activate CD4+ Th-lymphocyte precursors. Their major antiviral effect appears to be secreting cytokines and activating other effector cells, such as B-lymphocytes and CTLs. They may also have indirect antitumor activity via release of toxic cytokines (e.g., tumor necrosis factor-a [TNF-a]). CD4+ Th-lymphocyte help is crucial for the maintenance of an effective CTL response. When the infected cell is MHC class II-positive, CD4+ T-lymphocytes can also be cytolytic to the target cells (7). This function has been clearly demonstrated for herpesvirus infections including cytomegalovirus, herpes simplex virus, varicella-zoster virus, and EBV (8).

Endogenously synthesized antigens are generally thought to be presented as peptides on MHC class I molecules to CD8+ CTLs (i.e., the cytosolic pathway), whereas exogenous antigens are phagocytosed and presented in an MHC class II context to CD4+ Th-lymphocytes (i.e., the endosomal pathway). Alternatively, APCs can phagocytose antigens from virus-infected cells and present them on MHC class I molecules via exogenous pathways (6). Viruses possess mechanisms to enter the cytosol, and virion proteins, although not endogenously synthesized, can gain access to the MHC class I pathway (9,10). Thus, in some instances, the immune system might eradicate infected cells before the viral genome is expressed and progeny viruses produced.

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