Lecture 10: Major Histocompatability Complex & Antigen Presentation

antigen presenting cells

capture antigen that enters the body - express MHC on cell surface & display peptides bound to MHC to T cells

what is the key antigen presenting cell?

dendritic cells

immature dendritic cells reside in the ________ and mature on the way to the _________

reside in the tissue; mature on the way to the lymph nodes

immature DCs express ________ on their surface which...

CCR7; binds chemokines produced in the lymph nodes

mature DCs link the

innate and adaptive immune responses

what happens to DCs during maturation?

increased expression of MHC and costimulatory molecules

where do mature DCs reside?

T cell regions of lymph nodes (paracortex) and spleen (PALS)

major histocompatibility complex (MHC) AKA

human leukocyte antigens (HLA)

class 1 MHC locus: 3 genes that encode 3 proteins

HLA-A, HLA-B, HLA-C that encode HLA-A/B/C proteins

class 2 MHC locus: 3 genes that encode...

HLA-DP, HLA-DQ, HLA-DR that each contain alpha and beta genes that encode alpha and beta chains to form MHC2 proteins

class 3 MHC locus

includes genes for proteins involved in antigen processing, cytokines, and complement

MHC is ________, meaning...

highly polymorphic; meaning it enhances the capability of the population to defend against microbes

HLA haplotype

set of HLA alleles present on chromosome 6 inherited from each parent

HLA alleles are ________ expressed, to...

co-dominantly expressed, to maximize the number of MHC proteins available to bind peptides for presentation to T cells

T cell receptor

expressed on the surface of T cells - recognize peptides bound to MHC

TCRs consist of

alpha and beta chains

MHC restriction

T cell recognition is restricted to self MHC - an individual's T cells only recognize foreign peptides when displayed on self MHC

MHC1 is expressed on

all nucleated cells (so not RBCs)

MHC1 consists of

1 transmembrane chain: 1 alpha chain with a1, a2, and a3 domains and a B2m protein

alpha1 and alpha2 domains of MHC1 alpha chain consist of

polymorphic residues

what does the alpha3 domain of MHC1 alpha chain bind?

CD8 protein on CD8+ T cells

MHC2 is expressed on

DCs, macrophages, B cells ("professional APCs")

MHC2 consists of

2 transmembrane chains - 1 alpha and 1 beta

the _____ domain of MHC2 binds...

the beta2 domain binds CD4 protein on CD4+ T cells

MHC peptide binding cleft

contains pockets that anchor resides of peptides - the sides and top contact TCR

cytotoxic T lymphocytes (CTLs) express

CD8 (CD8+)

what do CTLs do?

kill cells presenting MHC1 antigen complexes on cell surface

what do helper T cells express?

CD4 (CD4+)

what do helper T cells do?

interact with DCs, macrophages, and B cells presenting MHC2 peptide complexes

MHC1 recognizes

intracellular protein antigen

5 general steps of MHC1 pathway

1. production of proteins in cytosol

2. proteolytic degredation of ubiquinated proteins

3. transport of proteins from cytosol to ER

4. assembly of peptide-MHC1 complexes in ER

5. surface expression of peptide-MHC1 complexes & presentation to CD8+ T cells

what is the role of the proteasome in the MHC1 pathway?

it is a protease that cleaves proteins in the cytosol into peptides

the proteasome targets _____ cells for proteasomal degredation

ubiquinated

what is the role of TAP in the MHC1 pathway?

it is an ATP-dependent peptide transporter in the ER membrane that transports peptides from the cytosol to the ER

what is the role of tapasin in the MHC1 pathway?

links MHC1 proteins to TAP

MHC2 recognizes

extracellular protein antigen

5 basic steps of MHC2 pathway

1. uptake of extracellular proteins into vesicular components of APCs

2. processing of proteins in endosomal/lysosomal vesicles

3. biosynthesis & transport of MHC2 to endosomes

4. association of processed proteins & MHC2

5. expression of peptide-MHC2 on cell surface & presentation to CD4+ T cells

what is the role of the invariant chain in MHC2 pathway?

binds MHC2 proteins in the ER to prevent peptides from loading in the ER and directs MHC2 proteins to endosomal compartment

the invariant chain is gradually degraded, until only ______ is left, which

CLIP; occupies the peptide-binding cleft of MHC2 proteins

what is the role of HLA-DM in MHC2 pathway?

facilitates loading of peptides into MHC2 in exchange for CLIP

all nucleated cells can present anitgen to __________, but DCs can present antigen to ________, which

effector CD8+ T cells; immature CD8+ T cells, which initiates the adaptive response & activates effector function

in MHC2, dendritic cells present antigen to

naive CD4+ T cells to initiate adaptive response & effector function

macrophages present antigen to

effector CD4+ T cells (cell mediated immunity)

B cells present antigen to

effector CD4+ T cells (antibody mediated/humoral immunity)

what is cross presentation? what response is it important in?

the ability of dendritic cells to present protein antigen from other cells via MHC1 to naive CD8+ T cells by phagocytosis of dying infected cells - important in responding to viruses

what are the 3 ways that non-protein antigen is presented?

1. presentation of small molecules and metal ions to T cells

2. presentation of lipid/glycolipid antigen to NKT cells

3. presentation of variety of antigen to gamma delta T cells

NKT cells recognize _______ presented by _______, which is a

lipids/glycolipids; CD1, a class 1-like novel MHC protein

what are superantigens and what do they do?

proteins (like bacterial toxins) that bind to MHC2 outside of the peptide binding cleft and to beta chains of TCR simultaneously to elicit polyclonal T cell activation causing a cytokine storm and T cell death

what is a cytokine storm?

production of mass amounts of cytokines, an immune system overreaction causing systemic inflammation