1. Antigen Presentation: Cells, Signals, and Resulting Immune Responses Michael Podolsky

2. Lecture overview
Objective: To understand the mechanisms by which naïve T cells are specifically activated, and the resulting phenotypes of antigen presentation.
Outline:
Background information on APCs and T Cells
Processing of antigens by APCs
Priming of naïve T cells by pathogen-activated dendritic cells
Properties of effector T cells 2

3. 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

4. Dendritic Cells, Macrophages, B Cells
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

5. Dendritic Cells, Macrophages, B Cells
Types of APCs:
Dendritic Cells, Macrophages, B Cells
Langerhans Cells:
Dendritic cells specific to the skin
Resident in the epidermis
High APC activity

6. Dendritic Cells, Macrophages, B Cells
Types of APCs:
Dendritic Cells, Macrophages, B Cells
Dendritic Cells:
green = MHCII
red = lysosomal protein
yellow = green + red

7. Dendritic Cells, Macrophages, B Cells
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

8. Dendritic Cells, Macrophages, B Cells
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

9. Distribution of APCs in lymph nodes

10. Dendritic Cells, Macrophages, B Cells
Types of APCs:
Dendritic Cells, Macrophages, B Cells
Summary of functions

11. Introduction: T Cells
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 11

12. 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.

13. 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

14. 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

15. Routes of antigen processing and presentation

16. Priming of naïve T cells by pathogen-activated 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)

17. Priming of naïve T cells by pathogen-activated 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

18. Priming of naïve T cells by pathogen-activated 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

19. 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)

20. 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.

21. 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

22. 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

23. Properties of Effector CD4 Cells

24. 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

25. Properties of Effector T Cells:
Summary

26. 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.