Immunology #9 - T-Cell Activation

Front 1

Effector CD4+ T cells

Back 1

- Secretion of cytokines
- Thp = naive CD4+ cells

Front 2

Where?

Back 2

Primary immune responses occur in secondary lymphoid tissues and lead to the generation of T cell subsets that secrete distinct patterns of cytokines

Front 3

Antigen Recognition and Molecular Interactions

Back 3

T-cells requires that the antigen be displayed on the surface of an antigen presenting cell in association with class II MHC (peptide/class II MHC)

Front 4

Dendritic cell

Back 4

- Most efficient antigen-presenting cell
- Expresses both class II MHC and various costimulatory molecules

Front 5

Signals for CD4+ Activation

Back 5

1. Peptide/class II MHC with TCR
2. Class II MHC with CD4
3. B7 family of costimulatory molecules with their counter ligands, CD28/CTLA4
4. CD40 with its counter ligand CD40L/CD154
5. Adhesion molecules

Front 6

Primary Response: Progression from CD4+ Naive T cell (Thp) to T cell Subsets:

Back 6

- TCR interaction with peptide/MHC II - naïve CD4+ T cells, Thp, express IL-2 receptors, and secrete the cytokine, interleukin-2 (IL-2)
- Interaction of IL-2 induces clonal expansion of antigen stimulated T cells, increasing # of T cells peptide/class II MHC
- Costimulatory signals from ligation of CD4 (or CD8) with class II MHC (or class I MHC) are also required for optimal T cell activation

Front 7

CD28 with CD80/CD86

Back 7

- Critical signal in T cell activation leading to clonal expansion
- T cell activation expression of CD28 initially increases, then is transiently down regulated

Front 8

CD80 (B7)

Back 8

- Ligand for CD28 exists in two distinct forms = CD80 and CD86/B7-1 and B7-2
- Both are constitutively expressed on dendritic cells and peritoneal macrophages
- Induced on activated B cells, monocytes, and Langerhans cells

Front 9

Classic Model of Thp cell Activation

Back 9

- Th0 cells secrete cytokines common to both subsets (IL-4, IL-2, and IFNγ)

Front 10

Th1 or Th2 cell phenotype

Back 10

Depends on several factors:
1. If IFNy = high, Th1
2. If IL-4 = high, Th2

Front 11

Source and Role of IL-4 (Non-T cell Derived Source)

Back 11

- Th0 populations are driven towards the Th2 and Type-2 cytokine secretion
- Type-2 cytokine = IL-5, IL-6, IL-4, IL-10, IL-13, TGF-B

Front 12

Source and Role of IFNγ (NK cell Derived)

Back 12

- Th0 cells to Th1 and Type-1 cytokine secretion
- Type-1 cytokines = IL-2, IFN-y, TNF

Front 13

IL-12

Back 13

- Produces IFNγ - indirectly increases Th1 and Type 1 cytokine secretion

Front 14

Type 1 cytokines vs. Type 2 cytokines

Back 14

- Type 1 cytokines = IL-2, TNF, IFNγ
- Type 2 cytokines = IL-4, IL-5, IL-6, IL-10, TGFβ, and IL-13

Front 15

Type 1

Back 15

- Macrophages, NK cells and CD8+ T cells
- Responsible for delayed type hypersensitivity responses that are manifestation of activation of memory CD4+Th1 cells (clinical section).
- Required for viruses, parasites, fungi, and intracellular bacteria.

Front 16

Type 2

Back 16

- B-cell induced activation and support antigen
- B-cell differentiation to plasma cells
- Support isotype switching to IgG1 and IgE (IL-4)

Front 17

IL-10

Back 17

- Down regulation of Th1 (cells/cytokines) via inhibition of IL-12 secretion

Front 18

T cell Regulation

Back 18

1. Peptide/MHC complexes are no longer being presented to T cells
2. Reciprocal regulation of cytokine secretion by Th1 and Th2 cells
3. CTLA-4/CD152 interaction
4. CD200-CD200R interaction
5. Apoptosis
6. Regulatory T cells (Tregs)

Front 19

Role of CTLA-4/CD152

Back 19

- Binds the B7 family members
- Apoptotic stimulus

Front 20

CD200

Back 20

- Ligand for CD200R1 and its isoforms
- Leads to suppression of T-cell-mediated immune responses
- CD200 expression on tumor cells suppresses anti-tumor cytotoxic immune responses

Front 21

CD200R

Back 21

- CD200R is expressed primarily on cells of the myeloid lineage (some T cells)
- C4+ T cells, memory cells express higher amounts of CD200R
- CD200R expression is up-regulated on both CD4+ and CD8+ T cells after stimulation.
- Interaction of CD200 with CD200R leads to suppression of the cell expressing CD200R

Front 22

Adaptive-Induced T Regulatory cells (a/iTregs)

Back 22

- a/i Tregs arise in the periphery following activation of Thp cells in the presence of TGFβ
- CD4+, CD25+, and FOXP3+

Front 23

CD4+ Th17 cells

Back 23

- Arise from Th0 cells in the presence of TGFβ and IL-6
- TGFβ and IL-1 may also induce the differentiation

Front 24

Summary of differentiation of Th17

Back 24

- NOTE: FINAL stage requires IL-23

Front 25

Secondary Response (Memory) T cell activation

Back 25

- Memory cells can serve an immunosurveillance role, having been pre-sensitized to the immunizing agent that induced their differentiation
- Memory CD4+ T cells secrete cytokines

Front 26

CD8+ T cell Activation (Antigen Induced differentiation)

Back 26

IL-2 and IFNγ induces differentiation of pCTL to CTL

Front 27

Costimulatory molecules for T-cell activation

Back 27

- CD2 and LFA-3, LFA-1 and ICAM (1-3)
- These are necessary

Front 28

Presentation of Peptide-Class I MHC

Back 28

- CD8+ T cells recognize peptide-MHC class I on the surface of any nucleated cell
- TAP-1 and TAP-2 - complex with Class I MHC in the endoplasmic reticulum

Front 29

Sequence of Events in Development of pCTL to CTL

Back 29

- Requires IL-2
- Differentiation of most pre-CTLs requires auxiliary activation of Th1 cells to provide a source of IFNγ and IL-2
- IL-2 functions in a paracrine manner to induce proliferation and clonal expansion of those pCTLs that express IL-2 receptors
- CTLs (hereafter termed CTLs) function in immune surveillance

Front 30

CTL cytotoxicity and delivery of lethal hit

Back 30

1. Formation of mature CTL with the target cell
2. Triggers the localization of lytic granules to the CTL membrane where the two cells are in contact
3. Polarization of granule release directed towards the target cell -ensures specificity of killing
4. Death of the target cell occurs by either osmotic lysis or apoptosis

Front 31

Perforin

Back 31

- Pore forming protein whose insertion into the target cell membrane leads to colloidal swelling and osmotic lysis
- Release of perforin dependent on calcium

Front 32

CD8+ T cell activation: Secondary Response (Memory)

Back 32

- After infection, some T cells become dormant = memory cells
- CD8+ T cells requires less costimulation than for primary responses
- Memory CD8+ T cells can occur anywhere that the T cell encounters a cell expressing the same Class I MHC-peptide that triggered its activation

Front 33

Activators of Lymphocytes

Back 33

Front 34

Superantigens

Back 34

- Superantigens crosslink the CD4+ T cell variable region, at a site that is independent of the peptide binding site, with class II MHC proteins
- Do not undergo processing and presentation by MHC molecules