Lecture 6 - Antigen Processing and Presentation: MHC and Dendritic Cells

what are MHCs?

major histocompatibility complex = genes that encode cell surface glycoproteins; ESSENTIAL for adaptive immunity

how do MHC molecules take part in adaptive immune response

MHC molecules bind peptide fragments from pathogens/self-proteins and present them on the surface of the cell to be recognized by the T lymphocytes

what characteristic of the MHC molecules allows it to increase the host’s ability to recognize diverse pathogens?

MHC genes are very polymorphic and polygeny

what is polymorphic mean?

many allelic variants within a population; polymorphism is concentrated mainly in the peptide-binding regions of MHC molecules that influences the peptide-binding specificity

what is polygeny?

where there are multiple MHC genes within each class - many genes influence the MHC molecule

veterinary species have ______ MHC nomenclature

unique

what are the two primary classes of MHC

MHC class I; MHC class II

where are MHC Class I expressed?

on almost all nucleated cells, presents endogenous peptides to CD8+ cytotoxic cells

where are MHC Class II expressed

mainly on professional antigen-presenting cells, presents exogenous peptides to CD4+ helper T cells

what are APC

antigen presenting cell - cell that captures and processes antigen to present to immune cells that can direct an adaptive immune response

what are the two types of APCs?

Professional APCs = phagocytic, localize to T cell zone of lymph nodes; constitutively express MHC II

atypical APCs = inducible expression of MHC II, limited to specific immune microenvironments

what type of cells have professional APCs

dendritic cells, macrophages, B cells

what type of cells have atypical APCs?

mast cells, basophils, eosinophils

what is the structure of MHC class I molecules

composed of 3 heavy chains - a1, a2, a3 - and B2-microglobulin

how are MHC class I molecules expressed

found on nearly all nucleated cells, levels of expression vary among cells; lymphocytes express them the highest

what is the specific function of MHC class 1 molecules

present peptides from EDOGENOUS proteins (viral, tumor-associated, or normal self-proteins) to CD8+ cytotoxic T cells - provides a snapshot of intracellular proteins to the immune system

how are the cytosolic proteins processed by the killer T cells in the antigen processing and presentation pathway (MHC 1)

• cytosolic proteins are degraded by the proteasome

• peptides are transported into the ER via the TAP transporter

• loaded onto the MHC 1 complex and transported to the cells surface

what is the veterinary relevance of MHC class 1 molecules

BoLA class 1 = cattle

SLA = swine

DLA class 1 = dogs

FLA class 1 = cats

Polymorphisms in MHC 1 genes can affect susceptibility to viral infections such as FIV in carts or PRRSV in pigs

what is the structure of MHC class 2 molecules

compose of 2 chains

• alpha chain - a1, a2

• beta change - B1, B2

both are transmembrane glycoproteins

how are MHC class 2 molecules expressed?

restricted to professional-presenting cells (APCs); can be upregulated upon activation during immune responses

what are the APCs

dendritic cells, macrophages, b cells

what is the specific function MHC class 2 molecules

presents exogenous peptides derived from extracellular pathogens or soluble antigens to CD4+ helper T cells

what do the helper T cells do after being presented the signal?

coordinate immune responses, including B ell activation, macrophage activation, and enhancement of cytotoxic T cell

what is the antigen processing and presentation pathway in MHC class 2 cells

• extracellular antigens internalized via endocytosis or phagocytosis

• degraded into peptides

• MHC 2 molecules are bound to invariant chain to block the peptide-binding groove (ER)

• chain degraded to CLIP in endosome and removed by the HLA-DM animal specific to allow binding of processed peptides

• stable peptide-MHC 2 complex transported to the cell surface for recognition by CD4+ T cells

what are some veterinary species considerations

• class 2 names equal class 1

• MHC 2 polymorphisms can influence susceptibility to bacterial and parasitic infections and vaccine efficacy

what is the origin of dendritic cells?

derived from bone marrow hematopoietic stem cells and differentiate through myeloid or lymphoid progenitor lineages, they migrate to peripheral tissues in an immature state, specialized for antigen capture

what are the subsets of dendritic cells

• conventional DC

• plasmacytoid DC

• Tissue specific DC

_______ are efficient at antigen presentation to T cells, including cDC1 and cDC2 subsets with differences in T cell priming ability

conventional DC

Plasmacytoid DC special in type I interferon production in response to _________

viral infection

_______ use Langerhans cells in the skin and mucosal DCs in respiratory and GI tracts

tissue-specific dendritic cells

what are the functional states of DCs

• immature DC

  • mature DC

what are Immature DCs

high antigen uptake capacity (phagocytosis, macropinocytosis, receptor-mediated endocytosis) but low MHC II and co-stimulatory molecule expression

what are the characteristics of mature DCs

triggered by PAMPs via PRRs such as TLRs, upregulate MHC molecules and co-stimulatory molecules, and migrate to secondary lymphoid tissues to present antigens to T cells

what is the role of DC in the immune response

• DC link innate and adaptive immune by detecting pathogens, processing antigens, and activating adaptive immune cells

• CRUCIAL for T cell priming via MHC molecules

• promote immune tolerance by inducing T cell anergy or regulatory T cells differentiation

what are the veterinary species consideration with DCs?

• DC subset distribution and PRR expression patterns vary between species influencing immune responses

  • vaccines often target DC activation through adjuvants that stimulate PRRs

what are the antigen uptake mechanisms that are performed by DC

• phagocytosis - engulfment of molecules

• macropinocytosis - nonselective uptake of extracellular fluid

• receptor-mediated endocytosis -specific uptake using receptors and complements

what is the antigen processing pathway in DC via MHC class 2

• antigens are internalized into endosome/lysosomes

• degraded into peptides

• loaded onto MHC II molecules to be expressed on the cells surface

• recognized CD4+ T cells

what is the antigen process of DCs via MHC class 1

endogenous proteins, DC use cross-presentation which allows exogenous antigens to be processed this way

• translocate to cytosol

• proteasomal degradation, peptide transport into the ER via TAP, loading onto MHC 1 and expression for CD8+ t cell activation

DCs are the _____ that can activate _______

ONLY APCs; Naive T cells

what are the 5 subtypes of DC

• plasmacytoid (pDC)

• classical type 1 (cDC1)

• classical type 2 (cDC2)

• follicular

• langerhans

pDCs have ______ precursors

lymphoid

cDC1 have _____ precursors

myeloid

what do pDCs and cDC1 produce large amounts of in response to a viral infection

interferon (IFN)

what are cDC2 and follicular DCs essential for?

• helper T activation (CD4+)

• antibody production

• development of B cell memory

• can be used not only for viral infections

which type of cells is important in allergy and skin hypersensitivity?

langerhans - trap pathogens in dermis

which DC is “king” in viral infection

pDC>cDC1>cDC2

after antigen capture and maturation, where do DCs migrate to from their peripheral tissue?

secondary lymphoid organs (lymph nodes, spleen)

what is the migration of the DC from peripheral tissue to secondary lymphoid organs?

chemokine receptor CCR7

how is the antigen presented by the DC to the T cell?

DC display peptide MHC complexes on their surface, the T cell receptor (TCR) on the T cell recognizes the peptide-MHC complex in an MHC-restricted manner

MHC 1 —>

CD8+ CTLs

MHC 2 —>

CD4+ helper T cells

what is the purpose of co-stimulatory molecules?

antigen recognition alone is insufficient for full T cell activation, provided by DCs wha

what are the co-stimulatroy signals

CD80/CD86 binding to CD28 on T cells (activation signal)

CD40 on DCs binding to CD40L on T cells, enhancing DC activation and IL-12 production

how do DCs use cytokine for signalling?

they secrete cytokines that influence T cell differentiation

what are the cytokines that are released by DCs?

• IL-12 —> Th1 responses (cell-mediated immunity)

• IL-4 —> Th2 responses (humoral immunity)

• IL-6,TGF-B, IL-23 —> Th17 responses (inflammation and extracellular pathogen defense)

• IL-10, TGF-B —> regulatory T cell induction for tolerance

what is the outcome of DC-T interaction?

production activation = effector T cell differentiation and memory formation

tolerance induction = without co-stimulation, T cells may become anergic or differentiate into Tregs

what is the veterinary significance of DC-T interactions?

in cattle - strong DC-CD4+ T cell interaction are critical for immunity against Mycobacterium bovis

in poultry - mucosal DC-T cell interaction play a key role in defense against avian influenza

what is cross-presentation?

the ability of certain DCs to present exogenous antigens on MHC I molecules to activate CD8+ CTLs (this is usually the normal process via MHC Class II

what is the importance of cross-presentation

• enables immune system to initiate CTLs responses against viruses and tumors when the DC itself is NOT infected

• critical for immunity to pathogens that do NOT directly infect DCs

• facilitates tumor antigen recognition and anti-tumor immunity

what are the two cross-presentation mechanisms?

• cytosolic pathway

• vacuolar pathway

what is the cytosolic pathway?

• exogenous antigens translocated from endosomes into the cytosol

• degraded by the proteasome into peptides

• peptides transported into the ER by TAP and loaded onto MHC I

what is the vacuolar pathway?

• antigens degraded within endosomal compartments

• peptides loaded directly onto MHC 1 molecules in endosomes without entering the cytosol

why are the mechanisms of cross-presentation relevant?

vaccine development that still induce cytotoxic T lymphocytes; targets DCs through species-adapted receptors can improve antigen delivery and immune activation

how does a DC know to perform cross-presentation?

• mix of innate programming (DC subset biology) and environmental cues (danger signals, type of antigen, route of uptake)

• some types of DC are specially built to do cross-presentation efficiently because they have the right tools

PAMPs detected viw TLR or other PRRs can _______ cross-presentation capacity.

upregulate

cytokines such as type I interferons enhance DC ability to _____________.

to process antigens via cross-presentation routes

give an example of how DC subset diversity varies by species?

Major DC subset are conserved across mammals, but their surface markers and relative abundance differ in veterinary species such as cattle, horses, dogs, and pigs

MHC molecules show ____ genetic diversity across species and breeds. What does this affect?

High; affects peptide binding repertoires and immune responsiveness

what are the major veterinary clinical considerations involving DCs and MHC?

• veterinary design and delivery

• immune evasion by pathogens - FIV exploits DC dysfunction or MHC downregulation to evade immune detection

• autoimmune and allergic diseases

• cancer immunotherapy - tailoring immunological approaches to species-specific DC biology and MHC diversity holds promise for advancing animal health

• transplantation and MHC matching