2.2.2 Antigen Processing and Presentation to T Lymphocytes
  • Processing of Antigen Is Required for Recognition by T Cells.
  • Most Cells Can Present Antigen with Class I MHC; Presentation with Class II MHC Is Restricted to APCs.
  • Significance of MHC-associated Ag presentation
    • T cell surveillance for foreign Ags inside and outside of cells.
  • Determination of which T cell subsets get involved in an immune response, therefore, determination of which effector mechanisms come into play
2.2.2.1 Antigen presenting cells(APCs)
Since all cells expressing either class I or class II MHC molecules can present peptides to T cells, strictly speaking they all could be designated as antigen-presenting cells. However, by convention, cells that display peptides associated with class I MHC molecules to CD8 TC cells are referred to as target cells;cells that display peptides associated with class II MHC molecules to CD4 TH cells are called antigen-presenting cells (APCs).
APCs for CD4+ T helper Cells
  • Professional APCs:
    • a) Dendritic cells (especially primary response)
    • b) Ms (mononuclear phagocytes) (particulate Ags)
    • c) B lymphocytes (can process specific Ags, by focusing Ag with their Ab receptors; secondary)
    • d) gamma/delta (/ T cells (recently seen to also act as APCs)
  • Non-professional APCs:
    • Vascular endothelial cells (some Class II; some co- stimulators)
    • Various epithelial and mesenchymal cells (some Class II; no co- stimulators).This may make them inefficient or differentialstimulators.
Cell type
Expression of
Principal function
 
 
Class II MHC
costimulators
 
 
Dendritic cells
Constitutive; increases with maturation; increased by IFN-
Constitutive; increases with maturation; inducibel by IFN-    ,CD40-CD40L interations
Initiation of T cells responses to protein antigens(priming)
Macrophage
Low or negative; inducible by IFN-
inducibel by lPS, IFN- ,CD40-CD40L interations
Effector phase of cell- mediated immune responses
B lymphocytes
constitutive; inducible by IFN-
inducibel by CD40-CD40L interations; antigen receptor cross-linking
Antigen presentation to CD4 helper T cells in humoral immune responses(cognate T cell-B cell interation
Vascular endothelial cells
inducible by IFN- ;constitutive in humans
Constitutive (inducible in mice)
May promote activation of antigen-specific T cells at site of angtigen exposure
Various epithelial and mesenchymal cells
inducible by IFN-;
Probably none
No know physiologic function
Roles of the APCs (Accessory Cells)
  • Antigen Processing and presentation : They convert protein Ags to peptides and display peptide-self MHC complexes on their surface for recognition by T cells (by their TCRs).
  • Costimulation: Some surface components of accessory cells engage "other receptors" on T cells and strengthen the binding or influence the ultimate response.
Professional APCs
Different functions of different types of APCs
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Dendritic cells
  • Dendritic cells are the most effective antigen presenting cells for initiating primary T cell response. Because these cells constitutively express a high level of class II MHC molecules and costimulatory activity, they can activate naive TH cells.
  • Now known to be critical for the initiation of an immune response by naive T cells, and thought to also control regulation or unresponsiveness.
  • Dendritic cell (DC) migration and its role in immunoregulation.The presentation of antigen by immature DC induces tolerance, instead of antigenspecific immunity. This may be brought about via two discrete mechanisms: by deletion of self-reactive T cells, or by the induction of anergic/regulatory T cells.
  • graphic
Macrophages
Macrophages express low levels of MHC II molecules, and much higher levels must be activated by phagocytosis of particulate antigens before they express class II MHC molecules or the costimulatory B7 membrane molecule.
B lymphocytes
B cells constitutively express class II MHC molecules but must be activated before they express the co-stimulatory B7 molecule. They use their antigen receptors(BCR) to bind and internalize soluble proteins and present processed pepetides to Th cells.
non-professional APCs
Several other cell types, classified as nonprofessional antigen-presenting cells, can be induced to express class II MHC molecules or a co-stimulatory signal. Many of these cells function in antigen presentation only for short periods of time during a sustained inflammatory response.
2.2.2.2 Process of antigen presentation
Rout of antigen entry, capture and presentation in vivo
  • Ags that enter through the skin or mucosal epithelial cells in the GI or respiratory tracts, drain down lymphatic vessels to LNs
  • Ags that enter through the blood   stream are “sampled” by the spleen.
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Antigen capture by APC and present to CD4 Th cells
  • Immature dentric cells are located in the epithelia of the skin and gastrointestinal and respiratory systems,which are the main portals through which microbe can enter.Upon encountering a pathogen, they rapidly mature and migrate to lymph nodes, go to the paracortical areas to mix with T cells because mature DC can express CCR7 which is specific for chemokine produced in T cell zone of dLN.
  • Activated T cells migrate to perpheral sites of inflammation or infection , where antigens are presented by macrophages and other APCs.
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Antigen presentation to CD8 T cells
  • CD8+ T cells see Ag in the context of MHC Class I molecules.
  • Essentially all nucleated cells of the body can express MHC Class I molecules and can act as “APCs” for CD8+ T cells.“APCs” for CD8+ T cells do not need to process extracellular Ags, but instead usually present Ags made in the cytosol(endogenously synthesized).
  • To be activated to proliferate and differentiate into CTL, naive CD8 T cells must recognize antigen-MHC I complex and also encounter costimulator on APCs or signals provided by CD4 Th cells. However, the main presentation pathway of DC cells is to present extracellular antigen to CD4 Th cells as an antigen-MHC II complex. Therefore, more likely a cross- presentation of antigens by APC to CD8 T cells is needed to initiate a primary repsonse. That is, virus -infected or tumor cells are captured by APCs, such as DC, and that the viral or tumor antigens are presented to naive CD8 T cells as antigen-MHC I complex.
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Cellular pathways of protein antigen processing and presentation
Two pathways:
  • Class II MHC pathway (MHC II-CD4 Th pathway)
  • Class I MHC pathway (MHC I-CD8 CTL pathway)
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MHC II-CD4 Th pathway
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antigen uptake
Immature DCs:
As part of the innate immune system, these cells have some Ag capture molecules (Fc & mannose receptors, TLRs, etc.)
Mature DCs:
Express co-stimulator molecules and augment their MHC expression; CCR7 receptor, too, which is specific for chemokine produced in T cell zone of dLN.
antigen processing
  • An endosome fuses with a lysosome, the pH drops & acidic proteases [Cathepsins & Acid Proteases] digest antigens into peptide fragments
  • Ag processing takes time and cellular metabolism that involves proteolysis. Raising the intravesicular pH also stops processing (as with CQ).
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MHC II synthesis and antigen loading
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Ii= invariant chain (non-polymorphic trimer)
CLIP= Class II-associated invariant chain peptide
The invariant chain (Ii) is a trimeric molecule that binds to MHC Class II a & b heterodimers via their "CLIP" portion in the MHC"peptide groove"-- when the heterodimers are first made in the ER
The class II-like protein HLA-DM binds to MHC Class II:CLIP complexes, catalyzing the release of CLIP --- - which then allows binding of the antigenic peptides in the MHC Class II groove.
Another class II-like protein HLA-DO may regulate the DM-catalyzed removal of CLIP.
surface expression
  • Surface expression of MHC molecules only happens if an antigen peptide occupies the groove.
  • Only a small number of the many MHC-peptide complexes on the surface will be any one peptide; and most will contain self- peptides.T cells survey APCs for foreign peptides vs. self peptides.T cells only need to see a few peptide-MHC complexes for activation & anti-self T cells are gone, inactivated, or controlled.
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MHC I- CD8 CTL pathway
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antigen uptake
Endogenously synthesized Ags (self-proteins, tumor Ags, intracellular pathogens) are degraded in the cytosol and transported to the ER.
antigen processing
  • Proteasomes:
Multiprotein enzyme complexes for degradation of proteins
    • Two catalytic subunits of some large (1500kD) proteasomes are LMP- 2and LMP-7: Encoded for by genes in the MHC; Up- regulated by IFN-g; Replace other subunits; Change substrate specificity to produce peptides of 6-30 AAs, often with carboxy terminal basic or hydrophobic AAs.
    • Proteasome inhibitors and mutations in LMP2 or LMP7 lead to susceptibility to some viruses.
  • Proteasomes are not enough:
Most peptides require further trimming after proteasome digestionBy Aminopeptidases & Tripeptidyl peptidase II (TPP II)in the cytosol and the Endoplasmic Reticulum as well.
MHC I synthesis antigen loading
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TAP:
Transporters Associated with Antigen Processing-1 & -2(TAP1 & TAP2).TAP1 & TAP2 genes are next to LMP2 and LMP7 genes within the MHC, and they too are up-regulated by IFN-g.
TAP delivers the peptides to the ER -- for binding in the Class I groove.
Chaperones:
Chaperones (calnexin, calreticulin) bind to MHC Class I achain until b2m binds.Other chaperones maintain MHC Class I as it binds to the TAP complex via tapasin
surface expression
Surface expression of MHC molecules only happens if an antigen peptide occupies the groove.
Presentation of non-peptide antigens
  • These nonprotein antigens(lipids/glycolipids) are presented by members of the CD1 family of nonclassical class I molecules.
  • T cells that express the gdTCR (T cell receptors are dimers of either ab or chains) that react with glycolipid antigens.
  • The CD1 family of molecules associates with 2-microglobulin and has general structural similarity to class I MHC molecules. There are five genes encoding human CD1 molecules (CD1A-E, encoding the gene products CD1a-d, with no product yet identified for E). These genes are located not within the MHC but on chromosome 1. Mice only have two CD1 molecules:CDd1 and CD1d2. They are grouped into two groups:
  • Group I:  present to T cells
  • Group II: present to NKT cells
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