Immunodominance and recognition of intracellular pathogens.

The concept of immunodominance during infection involves the generation of a focused immune response to a few of the many possible pathogen-derived antigenic determinants. The development of technical approaches to identify these antigens and predictive algorithms for major histocompatibility complex (MHC)– binding peptides have proven key in starting to dissect these events. When combined with the availability of MHC I and II tetramers to identify pathogen specific CD8 and CD4 T cells, these methods have provided many insights into the basic biology of an immune response. These approaches have revealed that a limited number of immunodominant epitopes account for the majority of the pathogen specific CD8 T cell responses for pathogens like Listeria, influenza, and HIV. Although this might be expected for organisms with small genomes, for more complex viruses and bacteria it is unexpected. Consequently, the question of why certain antigens become immunodominant has been a topic of much research over the last 30 years. Parasitic organisms are relatively large pathogens with complex life cycles that may involve migration through diverse tissues during development, and these organisms express literally thousands of proteins. Thus, it seems intuitive that during infections with such organisms, the immune system would recognize a multitude of pathogen-derived antigenic determinants. This is exemplified by studies with the opportunistic pathogen Toxoplasma gondii, an important cause of congenital disease and toxoplasmic encephalitis in immunocompromised individuals. CD8 T cells play a critical role in the control of this organism, and there have been numerous studies— using functional assays to measure cytokine production or cytolytic activity—that have focused on trying to identify which epitopes are recognized by CD8 T cells and which might be important vaccine candidates [1]. However, multiple attempts by several groups to identify class I–restricted epitopes to this opportunistic organism have been unable to do so. One of the reasons that contributed to this limited success was the lack of information and molecular tools to identify which parasite antigens might be involved in these processes. Recently, in an attempt to follow an endogenous immune response to T. gondii, several groups have utilized transgenic parasites that express various model antigens in conjunction with specific MHC tetramers and transgenic mice that express the T cell receptor for these antigens [2– 6]. While information obtained using these approaches has proven useful in understanding some of the events that regulate the evolution of the T cell repertoire as well as antigen presentation, it tells us little about the natural hierarchy by which pathogen antigens are recognized and whether this changes with time. In this issue of the Journal, Frickel et al. [7] used UV-sensitive caged tetramers to discover endogenous CD8 T cell epitopes to T. gondii. This technique, first described by Toebes et al., was used to identify T cell epitopes within the H5N1 influenza genome [8] and has since been used in human and mouse systems to characterize relevant class I–restricted epitopes from melanoma and Chlamydia, respectively [9, 10]. The ability to generate MHC molecules requires folding around an appropriate peptide to allow stabilization of the MHC molecule. Using conditional peptides that degrade after UV exposure allows complete MHC folding and safe removal of the conditional peptide without damaging the MHC molecule. If UV exposure occurs in the presence of a test peptide that is capable of binding in the empty MHC groove, this will generate a new class I–peptide complex. This peptide exchange process alReceived 5 August 2008; accepted 5 August 2008; electronically published 15 October 2008. Potential conflicts of interest: none reported. Financial support: National Institutes of Health (grant AI42334 to C.A.H.); State of California (start-up funding to E.H.W.). Reprints or correspondence: Dr. Christopher A. Hunter, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6008 ([email protected]). The Journal of Infectious Diseases 2008; 198:1579–81 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19811-0002$15.00 DOI: 10.1086/593020 E D I T O R I A L C O M M E N T A R Y