2. HLA (MHC) genes are codominant
and have multiple alleles
HLA’s are cell-surface proteins involved in the
recognition of self and non-self by the immune system
– important in determining histocompatibility for
transplantation
HLA’s present foreign antigens to the immune system
HLA’s are codominantly expressed
Multiple alleles of HLA in a population increases the
likelihood that the population will survive a pathogen
threat, also cause histoincompatibility in organ and
tissue transplants
3. Polymorphism and polygeny
• MHC genes are
polymorphic: that
is, there are large
numbers of alleles
for each gene
• MHC genes are
polygenic: that is,
there are a number
of different MHC
genes.
4. Class II MHC genes –pairs of class II a and b chains are DR, DP, DQ
– with extra DR-b chain, up to four types of class II MHC
Class III MHC genes – complement proteins C2, C4, factor B,
cytokine TNF-a, lymphotoxin TNF-b
Class I MHC genes
– three types of class I MHC a-chains are called HLA-A, HLA-B and HLA-C
“Non-classical” genes labeled in black; DM catalyzes peptide binding to MHC class
II molecules, DN and DO regulate DM, TAP and LMP are components of the
proteasome
Mouse and Human genomic map of MHC genes
5. Simplified comparison of
MHC genes in mouse and
human:
Class II MHC genes: encode glycoproteins expressed primarily on APC’s
(macrophages, dendritic cells and B cells) where they present processed
antigenic peptides to TH cells
Class III MHC genes: encode secreted proteins that have immune
functions e.g. components of the complement system and molecules
involved in inflammation, and other proteins
Class I MHC genes: encode glycoproteins expressed on the surface of
nearly all nucleated cells; present peptide antigens to TC cells
b2-microglobulin, which forms a complex with the MHC class I a-chains
is encoded on a separate chromosome
Chromosome 17
Chromosome 6
6. • Haplotype: the particular combination of MHC alleles found
on one parental chromosome
• Expression of MHC alleles is codominant, with protein
products expressed from both haplotypes in an individual
The many
combinations of
possible
haplotypes
contributes to the
difficulty of
finding
compatible
donors for tissue
transplantion
7. HLA genes are codominant: A protein from
each parental gene is expresed on cell-
surfaces
8. MHC molecules expressed on APC’s in a heterozygous mouse.
Both maternal and paternal genes are expressed.
9. MHC Expression
Class I
• Found on most nucleated cells
• Cells that express class I are called target cells
Class II
• Found on professional antigen presenting cells
• Dendritic cells, Macrophages and B-cells
10. • Class I MHC presents processed endogenous antigen to
CD8 (cytotoxic) T cells: CD8 cells are Class I restricted
• Class II MHC presents processed exogenous antigen to
CD4 (helper) T cells CD4 cells are Class II restricted
Professional
APC’s:
•B cell
•macrophage
•dendritic cell
Class I MHC
Class II MHC
Most
nucleated
cells
“Target cell”
TC cell TH cell
CD4
CD8
TCR TCR
11. Antigen Presenting Cells
• Dendritic Cells
• Macrophages
• B-cells
• Responsible for ‘activating’ T-Cells
• Do this by presenting antigen to naïve T-cells in
the context of MHC ALONG with co-stimulatory
molecules
13. T-Cell Activation
1: Interaction of T-cell receptor and CD4/8 on T-cells with MHC
loaded with peptide on the target cell
Encounter with antigen presenting cells initiates activation
2: Interaction of co-stimulatory molecule B-7 on antigen
presenting cells with CD28 on T-cell.
Activation requires that two signals be received
simultaneously:
Initiates a signal transduction cascade leading to extensive
transcriptional response and:
Proliferation
Differentiation
Cytokine production and secretion
14.
15. T cell Activation/Differentiation
•T cells require 2 signals
to activate them to divide,
and absolutely require IL-2 to
continue cell division
•Memory/Effector T cells
do not require Signal 2.
•The effector T cells carry
out specialized functions
-CD4+ TH cell:
cytokine secretion
and B cell help
-CD8+ CTLs:
cytotoxic killing
17. What are cytokines and chemokines?
• Small (10-30 kDa), usually secreted and usually
glycosylated peptides.
• They bind specific, high affinity (Kd of 10-10-10-12 M)
receptors found on target cells.
• Expression of cytokines and their receptors is usually
tightly regulated (i.e., temporally/ transiently and
geographically).
• Cytokine receptors define the specific type of biological
response cytokines stimulate.
• Other more anachronistic terms include monokines and
lymphokines. The term interleukin (IL) is now commonly
used(e.g., IL-1, IL-2, …).
18. What do cytokines, chemokines
and growth factors do?
• They direct the development,
maturation, localization, interactions,
activation and life span of immune cells.
• Thus they play an essential role in
regulating both immunity adaptive
and innate.
19. Important general properties of
Cytokines and Chemokines
• Usually stimulate transient responses.
• Function at three ranges:
– Autocrine - “self”
– Paracrine - adjacent cells
– Endocrine - through circulatory system
• Pleitropism - one ligand activate numerous types of
responses (e.g.,
differentiation, growth & activation).
• Redundancy - two or more ligands exhibit functional
overlap.
• Synergy - two or more ligands synergize to mount a
single response.
• Antagonsism - two or more cytokines mediating opposite
responses to either limit a response or achieve balance
(e.g. Feedback loops).
21. • Signal #1 (TCR)
and Signal #2
(coreceptors)
• direct activation
of naïve T-cells.
22. Cytokines & Chemokines can be grouped
into functionally related Families
• Cytokines can be divided into 6
functionally distinct groups.
• There are significant functional similarities
within each receptor family. The same is
true for corresponding ligands.
• There are important functional differences
between receptor families.
23. Six Functional Cytokine Groups*
• Growth Factors (e.g., CSF-1, SCF, RANKL,Flt3L)
• IL-1 Family (e.g., IL-1, IL-18 & “Toll-like”)
• TNF Family (e.g., TNF-α, CD40L, FasL, LT-β, BAFF)
• TGF-β Family (e.g., TGF-β )
• Chemokines (e.g., CC and CXC families)
• Type I & II Cytokines (a.k.a., Hematopoietins or
4 Helix Bundle Cytokines; e.g., IL-2, IL-4, IL-6, IL-10, IL-12,
GM-CSF, IFN-γ, IFN-α/β)
• Also steroid hormones and prostaglandins
32. The emerging story of
a new Tcell effector
pathway. . . . . .
the Th17 cell.
33. The Th17 Cell
• A CD4+ T-cell that arises from naïve CD4 cell.
• Secretes IL-6 and prodigious quantities of IL-17.
• Th17 cells probably evolved to combat pathogens not covered
by Th1 (intracellular) or Th2 (helminths) cells.
• IL-17 deficient mice are highly susceptible to extracellular
pathogens including Klebsiella, Borrelia and Citrobacter).
• IL-17 binds to a unique receptor expressed on many cell
types
– IL-17 stimulates fibroblasts, endothelial cells, macrophages,
and epithelial cells to produce multiple pro-inflammatory
mediators,e.g., IL-1, IL-6, TNF-α,NOS-2, metalloproteases, and
chemokines.
– IL-17 activates enhance granulocytes (innate immunity)
– IL-17 promotes cellular immunity by activating CD8 T-cells, NK
cells and macrophages.
• Implicated in autoimmune diseases (e.g., MS and RA).
34. Th17 Cell Maturation
• Antigen plus TGF-β and IL-6 direct CD4 T-cells into the Th17
lineage.
• IL-23 is also essential for Th17 maturation /activity.
• IL-23 is shares a 40 kDa subunit with IL-12 and binds to a
related but distinct receptor.
– IL-12 = p40 + p35
– IL-23 = p40 + p17
• Thus Th17 cells “appear” to be more closely related to Th1
cells
• IFN-γ and IL-4 inhibit Th17 maturation.
