Page 120 - Clinical Immunology_ Principles and Practice ( PDFDrive )

104 Part one Principles of Immune Response

in multiple allelic forms), this diversity of different peptide–class transpeptidation event, creating new epitopes from noncontiguous
II complexes displayed by APCs was unexpected. segments.
Several key features of MHC biology and biochemistry were Besides the interest in understanding the precise mechanism
revealed by this new technology. First, peptides derived from responsible for generation of these epitopes is the practical
alternative alleles of MHC proteins yield nonoverlapping sets implication of these events. Epitope identification often involves
of peptides. This permits assignment of peptide binding prefer- derivation and testing of overlapping peptide libraries from the
ences or motifs to different allelic and isotypic forms of MHC pathogen or tumor-derived proteins that are based on known
molecules (in humans, HLA-A, HLA-B, and HLA-C for class I, protein databases. The cryptic epitopes will not be represented
and HLA-DR, HLA-DQ, and HLA-DP for class II). This advance in these libraries, and accordingly, epitopes recognized by many
has enabled development and refinement of algorithms that potential effector CD8 T cells will fail to be identified. Thus
predict pathogen-associated epitopes as well as the definition of future vaccine strategies will need to take into account the prob-
preferred peptide-binding characteristics for MHC proteins that ability that some of the existing and potentially protective host
are associated with susceptibility to autoimmune disease or CD8 T cells may be dedicated to unpredicted peptides from
infection. Sequencing of the peptidome presented by MHC class pathogens or transformation.
II molecules also modified our view of class II presented peptides,
indicating that the bound peptides extend far beyond the CLInICaL reLeVanCe
exogenous pathway of antigen access. Many peptide epitopes
presented by class II molecules are now known to be derived Features of MHC Restricted Presentation that are
from cytosolic, nuclear, and membrane-associated proteins Important for Clinical and Translational Studies
synthesized within the APC. • Many viral- and tumor-derived peptides for CD8 T-cell recognition are
The discovery that antigenic peptides from vaccines, pathogens, derived from noncoding sequences, alternative reading frames, and
or transformed cells represent just a few of the hundreds to antisense coding segments.
thousands of self peptides presented on the surface of APCs • Vaccine strategies must take into account the need for linked recognition
supports the current view that the TCR must be capable of acute of B-cell and CD4 T-cell epitopes and also the selectivity of CD4 T-cell
discriminatory power and behaves more as a signaling protein responses that focus only on peptides that bind with very high affinity
on the class II molecule.
than a ligand-binding protein. With clarification of the diverse • Self tolerance within the thymus is selective for peptides that survive
nature of the peptides used for central tolerance induction, tapasin editing for class I presentation and DM editing for class II
tumor-specific antigens and peptides have been identified that presentation.
can be used for specific immunotherapy. And, methodology to • Autoantigenic peptides that escape self tolerance induction in the
allow sequencing of peptides from just a few million cells from thymus often have very low affinity interactions with MHC class II
the respiratory tract has led to the identification of respiratory molecules. This can make them difficult to identify or study with
MHC–peptide tetramers.
viral peptides presented by the HLA, offering new strategies for • Chronic viral infection frequently leads to downregulation of the
vaccine design. expression of MHC class I–peptide complexes. This leads to escape
from immune detection and destruction of infected cells by CD8
KeY ConCePtS T cells.
Viral Antagonists of Antigen Presentation
Pathogen Evasion Strategies
• Many viruses, particularly those that lead to chronic infections, encode Viral and bacterial pathogens employ extensive evasion strategies
multiple proteins that antagonize MHC-restricted antigen presentation. that to avoid immune recognition 43-45 (Chapters 24–26). A number
• Most viral evasion proteins inhibit MHC class I pathways needed
for CD8 T-cell recognition. of viral proteins, particularly those involved in chronic viral
• Some human immunodeficiency virus (HIV)–encoded proteins infections, interfere with components of the antigen presentation
antagonize class II–restricted presentation, as well. pathway. Many prevent peptide access to MHC class I molecules,
• Viral antagonists typically target the proteins most critical for presenta- which results in both immune evasion and greatly diminished
tion, including the TAP (for transporter associated with antigen process- cell-surface expression of class I molecules.
ing) transporter, tapasin, and the MHC molecule itself. For example, herpes simplex virus (HSV)– and EBV-encoded
proteins both interfere with the binding of peptide to the ER
localized TAP transporter. This blocks peptide transport to class
Cryptic Viral or Tumor-Associated Peptides Presented I molecules from the site of generation in the cytosol to the ER.
by MHC Class I Molecules The requisite ATP-dependent conformation change of TAP, needed
The transcriptome consists of the known translated sequence for peptide translocation from the cytosol to the ER, is also a
from a viral or endogenous self antigen. An increasing number target of viral antagonists. ATP activity is blocked by human
of tumor- and viral-derived peptides have been identified that cytomegalovirus (hCMV) US6 and EBV-derived BNLF2a. The
are not represented by the transcriptome. These cryptic peptides importance of tapasin in protective CD8 T-cell immunity is
are derived from many different molecular mechanisms, 40,42 evident by the ability of hCMV US3 to bind directly to it and
including alternate reading frames, translation of introns, antisense prevent tapasin-dependent loading of antigenic peptides. There
transcript encoded peptides, 5’ untranslated regions, and long are also numerous viral proteins that directly target MHC class
noncoding RNAs. In many cases, cytotoxic CD8 T cells have I for ER retention, such as adenovirus E3-E19, or degradation
been identified that recognize these peptides. For example, nearly directly from the site of synthesis in the ER. Finally, degradation
25% of epitopes from Simian immunodeficiency virus in rhesus of MHC class I molecules that have successfully emerged to the
macaques appear to be derived from translation of alternative cell-surface expression is promoted by viral proteins that mediate
reading frames. Perhaps most surprising is the discovery that polyubiquitination and targeting for lysosomal degradation
the proteasome can ligate distal peptides together through a (Kaposi sarcoma–associated herpes viruses Kk3/MIR1 and Kk5/