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M228: Biology of HIV
• Dr. Beth D. Jamieson
– 310-206-8217
– [email protected]
• Reading material: Course Reader Material
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You can’t understand HIV
pathogenesis without
understanding basic immunology
You can’t understand HIV
pathogenesis without
understanding basic immunology
WHY?
RAISON D’ETRE OF THE IMMUNE
SYSTEM:
To Distinguish Self from Non-Self Thereby
Protecting Us From Our Hostile Environment.
Innate Immunity
Adaptive Immunity
Innate immunity:
(Antigen
- nonspecific) defense
mechanisms that are used by
the host immediately or within
several hours of encountering
antigen.
Cells of the Innate Immune System
• Mast Cells – release of histamines,
hormones, chemokines. Important in inflammation and allergies.
• Neutrophils – phagocytosis
• Basophils – histamines
• Eosinophils - toxic proteins and free radicals
• Macrophages – phagocytosis & antigen presenting cells (APC)
• Dendritic Cells - phagocytosis & APC
• Natural Killer Cells – lysis of altered cells
 gd T-cells and iNKT- border between innate and adaptive immunity
Cells Use Surface Proteins to
Communicate
• CD: Cluster Designation (CD4, CD8, CD3)
• MHC: Major Histocompatibility Complex
encoded by chromosome 6 in humans.
Approx. 140 genes, ~70 of these are
involved in immune responses.
• HLA: Human Leukocyte Antigens. Is the
name of the MHC in humans =
interchangeable.
Cells Use Surface Proteins to
Communicate
• Antigen Receptors: Allows cells to
bind antigens with some specificity.
Antigen Presenting Cells
These specialized cells internalize antigen by
phagocytosis or endocytosis and then express
parts of the antigen on the cell surface. These
cells are distinguished by two properties:
1. Express class II MHC molecules (Helps in
in presentation of antigen)
1. Provide co-stimulatory signals necessary for
activation of T-cells.
Acquired Immunity
Is adaptive and displays four characteristic
attributes:
•Antigen specific
•Diversity
•Immunologic Memory
•Self/nonself recognition
Adaptive Immunity
Involves two major types of cells:
Lymphocytes:
a. Tcells
b. B cells
Antigen presenting cells: (APC)
a. Macrophages
b. B cells
c. Dendritic cells
Lymphocytes
B-cells:
•Produce antibodies and can present antigens.
•Are identified by the markers CD19 and CD20.
T-cells:
•Cytotoxic T cells kill infected cells.
•Are identified by the surface marker CD8.
•Helper T cells (Th) provide “help” for
Cytotoxic T cells and B cells.
•Are identified by the surface marker CD4.
Effector functions
Are induced following physical contact
with non-self:
•B cells secrete their antigen receptors:
antibodies.
•CD4+ T-cells secrete cytokines and
chemokines.
•CD8+ T-cells seek and kill cells that express
nonself and also secrete cytokines
and chemokines.
Cytokine:
“cyto” = cell,
“kine” = indicating movement
-intercellular messengers of the immune
system; regulate intensity and duration of
immune responses by:
stimulating or inhibiting the activation,
proliferation, and/or differentiation of
various cells regulating the secretion of
antibodies or other cytokines
-a.k.a. lymphokines (secreted by l’cytes),
monokines (secreted by mo),
interleukins (“between white blood cells”;
now up to IL-22).
Chemokine:
Small cyotokines that contain four cysteine residues.
They are chemotactic, they induce movement of cells.
APC
Antigen: ag
CD4+ T-cell
Lysis
Y
B-cell
Y
Death signals:
Perforin
Granzyme etc.
Cytokines
And
Interferon
Y Y
YY
CD8+ T-cell
YY
Clearance,
Neutralization
Cell mediated immune responses
Humoral responses
Lymphocytes cont.
T and B cells use specialized receptors to make
physical contact with non-self.
Although the structure of these receptors are
similar, they embrace non-self in very different
ways.
Cell Antigen receptor
Binding specificity
B cell Immunoglobulin (Ig)
Soluble antigen
T cell T cell receptor (TCR)* Processed antigen
*CD4+ T cells bind antigen with MHC class II
CD8+ T cells bind antigen with MHC class I
Immune responses are most efficient
in tissue parenchyma.
Lymph nodes and the spleen provide
architectural support for cell-to-cell
interactions, and serve as “filters” for
fluids draining other tissues.
Thymus
Spleen
Bone Marrow
Antigen Specificity:
Is determined by interactions between cellular
receptors (T-cell receptor and B-cell receptor
complex), antigen and human leukocyte antigens
(HLA).
Human Leukocyte Antigens:
Are encoded by the major histocompatibility
complex (MHC) on chromosome 6 in humans.
Class I antigens are found on all nucleated cells.
= A,B,C
CD8+ T cells recognize Class I antigens
Class II antigens are primarily on antigen presenting
cells (macrophages, dendritic cells and B cells).
= DR, DP, DQ
CD4+ T cells recognize Class II antigens.
Processing and presentation of antigens
Diversity
of the adaptive immune response is due to the
diversity of the T-cell and B-cell receptor
complexes.
Signal joint (sj) and coding joint (cj) TREC
production from the a/d locus
Va
Vd
dRec
Dd
Jd
Cd
yJa
Ja Ca
sjPCR
Douek et al. Nature 1998
cjPCR
MHC – peptide binding
T-cell recognition sequences
Anchor
Anchor
Anchor sequences bind to the MHC.
Peptide sequences effect MHC binding
and TCR recognition:
Binds MHC AndTCR
Loss or decrease In MHC binding
Loss or decrease in TCR binding
Antibody – antigen recognition
Antibodies recognize either linear epitopes or
epitopes in secondary structures. A change
is the amino acid sequence or secondary
structure can eliminate or diminish the antibody
binding.
No binding
Activation of T-cells requires signaling
through the TCR and co-stimulatory
molecules
APC
Class II
APC
Class II
CD80:86
CD4
CD4
CD28
T-cell anergy
T-cell activation
T-cell
TCR complex
B-cell
MHC class II
TCR and CD4
Engagement of
MHC and ag
Ag processed
For MHC
presentation
CD28
Engagement of
CD80/86
Upregulation
Of CD80/86
Upregulation
of CD40
CD40
engagement of
CD40
TCR complex
MHC class II
Memory
Is established through the clonal expansion of
activated T or B cells:
Self/nonself recognition:
Is achieved through the interaction of antigen
receptors, HLA, and antigen.
Responses to this complex are controlled through
A process of “education”.
Tolerance:
The inability to react with self.
Autoimmunity:
The state in which tolerance to
self is lost.
Take Home Points
• There are two arms of the immune system
• The immune system is designed to protect
us from pathogens like HIV
• HIV primarily infects cells of the immune
system
• Know the major functions of each major
lymphocyte type
• Understand how the body responds to an
antigen