Immunology #3 - Antigen Presenting Cells

Front 1

Antigen presentation

Back 1

- For effective presentation, an antigen fragment is displayed within the groove of special antigen presenting molecules
- These antigen presenting molecules are proteins encoded by the MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)

Front 2

Antigen presenting cells

Back 2

- Dendritic cells (most efficient during primary response)
- Macrophages
- B cells

Front 3

Immature dendritic cells

Back 3

Express:
- High concentrations of FcγR
- Low concentrations of both class II MHC and costimulatory molecules (e.g. B7-1, B7-2)

Front 4

Dendritic cells

Back 4

- Derived from CD34+ bone marrow stem cells
- Can be generated in vitro from blood monocytes or from CD34+ hematopoietic stem cells (HSC) in the presence of GM-CSF and other cytokines
- Express CD4
- Capture antigen in the periphery and transport it to the appropriate lymphoid tissue

Front 5

CD4

Back 5

- 1 receptor for the human immunodeficiency virus, type 1 (HIV-1)
- Infection with HIV-1 is initiated by interaction of viral envelope proteins with (at least) two receptors, the CD4 molecule and a chemokine receptor, CCR5 and/or CXCR4

Front 6

Macrophages

Back 6

- For primary immune responses the macrophage is NOT as effective in antigen presentation as the dendritic cell
- Express CD4 and the chemokine receptors CCR5 and/or CXCR4
- Macrophage activation upregulates Class II MHC and costimulatory molecules

Front 7

B cells

Back 7

- B cells recognize antigen via antibodies
- Antigen recognition by B cells is so specific, B cells can bind antigen even when it is present in low concentration
- B cells serve as the predominant antigen presenting cells when antigen is limiting

Front 8

Class I MHC molecules

Back 8

All nucleated cells express class I MHC molecules

Front 9

Class II MHC molecules

Back 9

Only professional antigen presenting cells express MHC II

Front 10

MHC

Back 10

- Located on chromosome 6
- In humans, the class I MHC molecules are encoded by three loci (A, B, and C)
- Class II MHC molecules are encoded by a “D” locus subdivided into 3 loci: DP, DQ, and DR

Front 11

General Features Polymorphism

Back 11

- Genes encoding each MHC locus are present in multiple forms (alleles) within the population
- The likelihood that 1 of the MHC alleles present in individuals within a population will bind to, and present, an antigen fragment of any particular microorganism to T cells, is increased by the existence of numerous alleles
- Differences in susceptibility to infection are believed to be a reflection of unique presentation of antigen to T cells by the MHC of susceptible versus resistant individuals

Front 12

Role of Class II MHC Molecules and Class II MHC Restriction

Back 12

- Class II MHC molecules present antigen to CD4+ T cells
- CD4+ T cells ONLY recognize antigenic peptides if they are displayed with Class II MHC molecules present on the surface of so-called “professional” antigen presenting cells
- CD4+ T cells are RESTRICTED to “see” antigen in association with class II MHC = class II MHC restriction

Front 13

Structure of Class II MHC molecules

Back 13

- Heterodimer consisting of two transmembrane polymorphic polypeptide chains (~29 kd each) in non-covalent association
- DP, DQ, and DR, are structurally similar and each binds antigenic fragments that vary between 15 to 30 amino acids in length

Front 14

Invariant chain - MHC II

Back 14

- Transiently associates with class II MHC molecules in the endoplasmic reticulum, forming a trimeric complex (class II MHC heterodimer and Ii).
- This invariant chain blocks the binding of superfluous peptides that the MHC heterodimer might encounter in the endoplasmic reticulum.
- Serves to direct the transport of class II MHC molecules through the golgi, from where they are released within endosomes

Front 15

Features of MHC I & II

Back 15

Front 16

Codominance of MHC II

Back 16

Codominant expression of HLA molecules means that one copy of each HLA (DP, DQ, and DR) inherited from each parent will be expressed. Therefore a minimum of six different class II molecules will be expressed on the cell surface providing the parents are genetically unrelated.

Front 17

Class I MHC molecules: Role of Class I MHC Molecules and Class I MHC Restriction

Back 17

- Infected cells are identified for destruction by CD8+ T cells following expression of a complex on the target cell surface, composed of an antigen fragment displayed in association with class I MHC molecule.

Front 18

Structure of Class I MHC

Back 18

- Each class I MHC molecule is composed of a transmembrane polymorphic polypeptide “heavy” chain (~45 kd) non-covalently associated with a smaller polypeptide (~12 kd), termed β2−microglobulin (nonpolymorphic molecule)

Front 19

Codominance of I MHC

Back 19

- In humans, the class I MHC molecules are HLA-A, HLA-B, and HLA-C, each of which is codominantly expressed on all nucleated cells
- Codominant expression of HLA molecules means that one copy of each HLA (A, B, and C) that is inherited from each parent will be transcribed and translated into protein

Front 20

Exogenous Antigen Processing and Presentation by Class II MHC

Back 20

1. Uptake of antigen by antigen presenting cells
2. Fusion of the endocytotic vesicle with lysosomes that release their contents into the endosome.
3. 2nd fusion process creating a chimeric endosome - class II MHC/Ii complex is exposed to lysosomal enzymes, 4. Li chain is degraded, and an antigenic peptide binds in the newly exposed groove of the class II MHC.
5. The chimeric endosome migrates to, and fuses with, the cell membrane
6. When these complexes are recognized by T cell receptors present on CD4+ T cells - activated to secrete cytokines

Front 21

Endogenous Antigen Processing and Presentation by Class I MHC

Back 21

- Cytosolic proteins are targeted for degradation following the attachment of ubiquitin, a small peptide found in the cytosol of all cells.
- Peptide fragments generated by the proteasome, in turn, bind to the transporter of antigen processing (TAP) proteins, and are transported into the endoplasmic reticulum, where they contact coassembled class I MHC molecules
- Complexes are released from the GOLGI into vesicles that fuse with the cell membrane

Front 22

Cross Presentation: Exogenous Antigens and Presentation by Class I MHC

Back 22

- Exogenous antigens normally processed in phagolysosomes and presented on the cell surface, are instead presented by Class I MHC molecules
- Mediated primarily by dendritic cells
- Exogenous antigens can be presented with Class I MHC, to CD8+ T cells

Front 23

Viral Sabotage of Antigen Processing & Presentation by Class I MHC Molecules

Back 23

Sabotaging the expression of the peptide/class I MHC complexes on the cell surface effectively protects the virus and the infected cells can serve as veritable “factories and reservoirs” for viruses.

Front 24

Herpes simplex virus (HSV)

Back 24

- Neurons express little cell surface class I MHC molecules, and so they provide a relatively safe haven for viruses
- Recurrent infections of non neuronal tissues can occurs because HSV also produces an immediate early protein that binds to the cytosolic portion of the TAP transporter. - Inhibits TAP-mediated translocation of peptides from the cytosol into the ER
- In the absence of peptide transport to ER, antigenic peptide/class I MHC complexes do not form, and the infection (by virus) in the cell remains undetected

Front 25

Epstein Barr virus (EBV)

Back 25

- One of the mechanisms by which EBV thwarts the immune system is by inhibiting the activity of proteasomes
- Virus prevents hydrolysis of viral proteins into peptide size fragments
- Only peptides (antigenic fragments) of a suitable size can bind in the “groove” of class I MHC molecules
- Whole virus, or even whole viral protein, is too large to bind in this groove - EBV remains safely sequestered in the B cell

Front 26

Cytomegalovirus (CMV)

Back 26

- Member of the herpes family, infects immunocompetent individuals without causing symptoms
- In immunocompromised individuals, infection with CMV may cause numerous disorders including encephalitis, pneumonia, hepatitis, retinitis or blindness
- CMV encodes proteins that redirect newly synthesized class I MHC molecules from the ER back into the cytoplasm where they themselves are degraded by the proteasome

Front 27

Nonresponsiveness

Back 27

Determinant Selection is a term used to describe a phenomenon in which the MHC molecules present on the cell do not bind a particular peptide and so that peptide cannot be presented to T cells

Front 28

CD1 molecules as Antigen Presenting Molecules

Back 28

- CD1 molecules are glycoproteins that present lipid and glycolipid antigens (e.g., mycobacterial phospholipids, glycolipids) to subsets of T cells
- Structurally the CD1 molecules are similar to Class I MHC in that they form a complex with β2 microgloblin
- Consists of 5 members that can be divided into two groups CD1a, CD1b, CD1c, and CD1e
- All CD1 proteins have a group of hydrophobic amino acids in hydrophobic pockets which can interact with hydrophobic molecules (e.g., lipids)