Immunotherapy for Infectious Diseases

260 Sili, Heslop, and Rooney
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