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CHaPter 6 Overview of T-Cell Recognition 105

MIR2 and EBV BILF1). Together, these and other mechanisms compartments accessed later during biosynthesis of the MHC
prevent detection by CD4 and CD8 T cells and the ensuing protein. Within each of these compartments resides a set of
protective immune response. proteins that participate in and direct peptide loading. Both
class I and class II molecules acquire peptides inefficiently, and
Tumor Escape From Immune Surveillance accordingly both require critical protein cofactors that prepare
Tumor progression is often associated with alterations in the the MHC protein to capture peptide. The presentation events
46
expression and/or function of the MHC class I molecules. Loss are also similar in that they allow only a subset of the potential
of DNA binding factors needed for promoter activation can lead self or pathogens peptides to be presented. Peptide editing of
to altered class I transcription. Loss of β2m gene expression can the repertoire of peptides presented by MHC proteins is primarily
lead to a global defect in class I protein expression at the cell based on the ability to stably interact with the MHC protein.
surface. Downregulation of the components of the constitutive
and immune-proteasome have been identified in a number of on tHe HorIZon
cancers. Low levels of TAP transporter components and the ER
aminopeptides (ERAAP) have been seen in others. Loss or • New means to regulate class II antigen presentation could come from
diminution of class I presentation of peptides is often associated a better understanding of the mechanisms by which HLA-DO regulates
HLA-DM or from the elucidation of new mechanisms by which
with disease progression, metastasis, and a detrimental clinical viral or bacterial products antagonize the MHC class II presentation
outcome in part as a result of evasion of immune detection and pathway.
impaired elimination of the transformed cells. • New means to regulate class I antigen presentation could come from
a better understanding of the mechanisms used to regulate proteasome
Potential Role of “Peptide Editing” of Presented generated cytosolic peptides and their transport by TAP (for transporter
Peptides on Self Tolerance and Autoimmunity associated with antigen processing) to MHC class I molecules and
from a better understanding of cross-presentation.
HLA-DM edits the repertoire of peptides presented by HLA-class • A better understanding of the similarities and differences in antigen
II molecules at the cell surface. These are the only peptides that presentation by the various APC subsets could lead to new vaccination
are available to interact with circulating CD4 T cells. Tapasin methods.
appears to have a similar function for MHC class I peptide • A better understanding of the role of cryptic peptides in CD8 T-cell
binding, enriching for presentation of peptides that bind with selection events could lead to the manipulation of CD8 T-cell responses
high affinity with the MHC class I molecule. This selective peptide to tumors, viruses, and autoantigens.
display by MHC molecules has important implications for self
tolerance and autoimmunity. Tolerance to self arises as a con- Because of MHC polymorphism, the peptides selected for
sequence of deletion of developing T cells whose TCR recognizes protection, self tolerance, and autoimmunity will vary from one
self peptides presented by host MHC molecules within the thymus individual to the next. Many pathogens have developed specific
(Chapter 8). This is termed central tolerance. Accordingly, central proteins that degrade or interfere with the essential functions
tolerance can only be operative if a self peptide is displayed at of the protein cofactors that regulate MHC-restricted antigen
the cell surface of APCs in the thymus. The bone marrow-derived presentation. These viral evasions strategies allow the infected
MHC class II and MHC class I positive APCs responsible for host cell to avoid immune recognition and destruction by CD8
deletion of self-reactive cells express the HLA-DM and tapasin and CD4 T cells. Interference with antigen presentation also
proteins and thus will only express peptides that bind with high leads to the escape of host cells from tumor-specific surveillance
affinity to MHC class II molecules. Therefore the host is selectively and allow progressive growth and metastases.
tolerant only to host peptides that survive this intracellular editing We now understand many of the key players in MHC-restricted
during biosynthesis of the MHC proteins. Self peptides that are presentation of antigen to CD4 and CD8 T cells. In the future
removed from MHC molecules during endosomal DM editing this understanding will be used for vaccine design strategies,
or ER-associated tapasin editing are essentially invisible to and in personalized medicine aimed at enhancing immunosurveil-
developing T cells. T cells that have escaped deletion in the thymus lance and protection mediated by the adaptive immune response.
will seed the peripheral pool of circulating T cells. The mature
CD4 and CD8 T cell repertoire therefore maintains reactivity ACKNOWLEDGEMENT
to some self peptides. Events in the periphery that modify
presentation of this subset of lower affinity peptides for MHC With the permission of authors J. Rodgers and R. Rich, the section
molecules will thus allow their display at the cell surface potentially of this chapter that discusses the nature of antigens was repro-
leading to recognition by host CD8 or CD4 T cells and thus duced, with modification, from Chapter 6 of the 4th edition of
initiation or propagation of autoreactivity. Clinical Immunology: Principles and Practices.

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The intracellular events involved in MHC class I and class II details.
restricted antigen presentation have many commonalities,
although they are different in the details. Both can be considered REFERENCES
three-chain proteins, where the bound peptide is the third chain.
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acquisition: For class I molecules, it is early in biosynthesis 3. Desai SN, Clemens JD. An overview of cholera vaccines and their public
within the ER, and for class II, it is within acidic endosomal health implications. Curr Opin Pediatr 2012;24:85–91.