Transcript Janeway*s Immunobiology Chapter 8: T cell

Antigen Presentation: Cells, Signals, and Resulting
Immune Responses
Michael Podolsky
Lecture overview
• Objective: To understand the mechanisms by which naïve T cells are
specifically activated, and the resulting phenotypes of antigen
presentation.
• Outline:
I.
Background information on APCs and T Cells
II. Processing of antigens by APCs
III. Priming of naïve T cells by pathogen-activated dendritic cells
IV. Properties of effector T cells
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Antigen Presenting Cells
• Antigen presenting cells (APC)
• 3 Types:
• Dendritic cells
• Take up antigen in tissues
• Migrate to secondary lymphoid tissue
• Mature in lymphoid tissue to express co-stimulatory
surface molecules
• Macrophages
• Engulf foreign bodies through phagocytosis
• Immature in tissue (Called Monocytes)
• B cells
• Recognize specific soluble antigens
http://www.biolegend.com/media_asset
s/aob_detail/dendritic_cells_category/d
endritic.png
Types of APCs:
Dendritic Cells, Macrophages, B Cells
Dendritic Cells:
• The primary APC in the body
• Survey tissues at all times (Healthy and infected)
• Take up antigen in the tissues
• Immature in tissues
• Become mature in lymphoid tissue following T cell
binding (CD40/CD40L)
- To be discussed later
• Originally thought to be part of the nervous system.
• Types of dendritic cells:
• Conventional dendritic cells
• Antigen presentation, Naïve T cell activation
• Plasmacytoid dendritic cells
• Produce mainly type 1 interferons
• Assists in viral infections
• Low antigen presentation ability
Types of APCs:
Dendritic Cells, Macrophages, B Cells
Langerhans Cells:
• Dendritic cells specific to the skin
• Resident in the epidermis
• High APC activity
Types of APCs:
Dendritic Cells, Macrophages, B Cells
Dendritic Cells:
green = MHCII
red = lysosomal protein
yellow = green + red
Types of APCs:
Dendritic Cells, Macrophages, B Cells
Macrophages
• Resident in tissues and lymphoid organs
• Prior to activation, circulate in the blood as immature cells (Monocytes)
• In healthy tissue: resting cells (No expression of costimulatory molecules)
Activation occurs upon ingestion of antigen
• Primarily through phagocytosis
• Recognition of pathogen associated molecular patterns (PAMPs)
• Leads to expression of costimulatory molecules and APC function
http://cdn.c.photoshelter.com/imgget/I0000tKWhLds70PU/s/600/600/228417.jpg
https://srxa.files.wordpress.c
om/2010/09/macrophage2.jpg
Types of APCs:
Dendritic Cells, Macrophages, B Cells
B Cells
• Part of adaptive immunity
• Known for antibody production, but have very efficient APC activity
• Recognize soluble antigens
• Ingest antigens through receptor mediated endocytosis
• Costimulatory molecules inducible, similar to dendritic cells
• Requires a signal from T cell for full APC function
Distribution of APCs in lymph nodes
Types of APCs:
Dendritic Cells, Macrophages, B Cells
Summary of functions
Introduction: T Cells
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Lymphocytes that begin development in bone marrow, mature in Thymus
T Cells in thymus are mature, but naïve (Not Ag experienced)
Recirculate between blood / secondary lymphoid tissue
Part of the adaptive immune system
• Naïve T cells become Effector T cells following activation
• Exposure to APC in secondary lymphoid tissue (Priming)
• 3 signals:
• Signal 1 (Ag:TCR)
• Signal 2 (costimulation)
• Signal 3 (cytokines)
• Only act on target cell (not on pathogen)
• Why it’s called “Cellular Immunity”
• Effector T cells: 5 classes:
• CD8+ (CTLs): cytotoxic
• CD4+ (Helper T Cells): Th1, Th2, Th17, Treg
https://upload.wikimedia.org/wikipedia/commons/6/62/Healt
hy_Human_T_Cell.jpg
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Processing of antigens by APCs
• Foreign objects are
recognized by a number
of processes
• Opsonization (Ab or
complement)
• Cell surface proteins
• APCs ingest foreign
bodies through
phagocytosis.
• Phagosome fuses with
lysosome
• Causes breakdown to
component peptides.
Processing of antigens by APCs
• MHCI
• Endogenous proteins
digested by proteasome
• Fragments transported
to ER through TAP1/2
• Trimmed, packaged
with MHCI
• Sent to golgi for
targeting to plasma
membrane
http://www.nature.com/nri/journal/v7/n7/fig_tab/nri2103_F2.html
Processing of antigens by APCs
• MHCII
• Phagosome fuses with
lysosome
• Digests to component
peptides
• MHCII formed in ER,
targeted to
phagolysosome
• Packaged with peptide
• Targeted to plasma
membrane
http://www.nature.com/nri/journal/v7/n7/fig_tab/nri2103_F2.html
Routes of antigen processing and
presentation
Priming of naïve T cells by pathogenactivated dendritic cells
• APCs expressing peptides
in context of MHC travel to
secondary lymphoid tissue.
• T cells transiently sample
antigen.
• If match is found,
interactions strengthen to
prolong contact (Days)
http://www.nature.com/nri/journal/v6/n9/images/nri1869-f1.jpg
Priming of naïve T cells by pathogenactivated dendritic cells
• T Cell activation
requires 3 signals:
• Signal 1:
Peptide/MHC::TCR
• Signal 2: Costimulation
(CD40::CD40LCD80/8
6::CD28)
• Signal 3: Cytokines for
determination of
activity
http://www.nature.com/mt/journal/v19/n1/fig_tab/mt2010250ft.html
Priming of naïve T cells by pathogenactivated dendritic cells
• Cytokines determine the function of the CD4 T cell following
emigration from lymphoid tissue
• Can be pro or anti inflammatory.
• Perpetuate or dampen immune responses
• Both are important for maintaining homeostasis
Janeway’s
Immunobiology:
Chapter 8
Properties of Effector T Cells:
Th1
• Effectors against intracellular bacteria and
protozoa.
• Activate Macrophages and CD8 T cells
• Primarily secrete IFNγ
• Overactivation leads to Type 4 delayed-type
hypersensitivity (More in later lectures)
Properties of Effector T Cells:
Th2
• Immunity against extracellular parasites: helminths
• Activate B cells and stimulate them to become
plasma cells (Antibody secretion)
• Indirectly stimulate mast cells to secrete histamine
• Secrete IL-4, IL-5, IL-9, IL-13
• Overactivation causes Type 1 IgE-mediated
hypersensitivity.
Properties of Effector T Cells:
Th17
• Maintain immunity in mucosal barriers (Gut, nasal
passages)
• Recently discovered, still much to learn.
• Implicated in autoimmune and inflammatory
disorders.
• Secrete IL-17
Properties of Effector T Cells:
TReg
• Anti-inflammatory
• Dampen immune responses to prevent tissue
damage
• Secrete IL-10, TGFβ
• Especially important in gut, prevent damaging
immune overactivation to innocuous antigens from
microbiome.
• Loss of function results in autoimmunity
Properties of Effector CD4 Cells
http://www.frontiersin.org/files/Articles/102119/fimmu-05-00276-HTML/image_m/fimmu-05-00276g001.jpg
Properties of Effector T Cells:
CD8
• Also known as Cytotoxic T Lymphocytes (CTLs)
• Stimulated by MHCI recognition and Th1 help
• Kill infected cells to prevent spread to infection.
• Secrete perforin, granzymes, granulysin.
Janeway’s Immunobiology: Chapter 8
Properties of Effector T Cells:
Summary
Lecture Summary
• 3 types of APC: Dendritic cells, Macrophages, B
cells.
• Each distributed differently in lymphoid tissue and
mediate different effects on T cells.
• Antigens can be presented in context of MHCI (CD8
Activation) or MHCII (CD4 Activation).
• Activation of T cells requires 3 signals:
• Signal 1: MHC/TCR recognition
• Signal 2: Costimulation
• Signal 3: Cytokine polarization
• Each effector subset has distinct functions, all of
which must be regulated to prevent autoimmunity
or hypersensitivity.