Lecture 9.docx

7/28/2019 Lecture 9.docx

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Lecture 9: T-lymphocyte Activation

1. T-cell quick review/overview

a. T-cells migrate from the thymus

b. Undergo antigen induced differentiation outside of the thymus

c. Start the primary immune response in secondary lymphoid organs

i. Subsequent exposure to the same peptide/Class II MHCinduces reactivation of memory cells, i.e. the secondary

immune response.

d. Antigen induced activation of T-cell requires an APC, such as the

efficient dendritic cells, and a set of interactions.

i. Peptide/class II MHC with the TCR

ii. Class II MHC with CD4

iii. The B7 family of costimulatory molecules

1. Key signal to begin T-cell differentiation

a. CD28 interacts with CD80/86 [B7]

i. Stabilizes mRNA for IL-2

iv. CD40 with it’s counter ligand CD40L/CD154 v. Various adhesion molecules

2. CD4+ T-cell activation (You must know what each cell produces!)

a. i. The process begins with a dendritic cell presenting to Thp.

ii. This is the crucial signal that causes CD28 to interact with

CD80/86.

1. This stabilizes the mRNA for IL-2

iii. IL-2 beings to be produced and causes Thp to become Th0.

iv. Dendritic cells begin to produce IL-12.



b. i. The IL-2 produced by Thp causes it to become Th0 cells.

1. These produce Il-2, Il-4 and IFN γ

ii. The IL-12 produced by the dendritic cell causes NK cells to

secrete IFN γ

c. i. Th0 cells can become either Th1 or Th2 cells.



1. If IFN γ predominates Th1 cells are produced.

2. If IL-4 predominates Th2 cells are produced.

a. IL-4 as you can see is also produced by Mast

cells.

d. i. Depending on which cell arises you get different cytokines.

1. Th1 produce Type 1 cytokines

a. IL-2, IFN γ, and TNF.

2. Th2 produces Type 2 cytokines.

a. IL-4, 5, 6, 10, 13, TGFβ

3. Jobs of Type 1 and Type 2 cytokines

a. Type 1 supports immune responses in which macrophages, NK cells,

and CD8+ T-cells are working.b. Type 2 is required for immunity against viruses, parasites, fungi, and

intracellular bacteria.

i. Also supports B cell induced activation and induced B cell

differentiation to plasma cells.

4. Cytokine interrelation in T-cell activation

a. IL-4 and IL-10 downregulates Th1 via inhibition of IL-12 secretion.

b. IFN γ downregulates Th2 response.



5. So once CD28 binds to CD80/86 interact they go forever right?

a. Wrong. As the immune response is not needed to fight invaders we

have to have a way to stop the immune system.

b. CTLA-4/CD152 binds more strongly to CD80/86 than CD28.

i. So when the process needs to be halted CTLA-4/CD152 is

produced and it unseats CD28 from CD80/86 causing T-cellactivation to cease.

1. CD28 is expressed constitutively while CTLA-4/CD152

is not; this is why the immune response can go on

initially. If we always had it then we could not mount an

immune response.

6. CD200 and CD200R(eceptor)

a. CD200 is a ligand while CD200R is a cellular receptor

b. These interact to suppress T-cell mediated immune responses

i. Also later it will be discussed in regards to cancer

c. The cell with the CD200R is the target for suppression! *

i. When CD200/CD200R bind the cell with the receptor issuppressed.

7. More nTreg info

a. Made up of CD4+, CD25+, FOXP3+

i. A separate lineage in the thymus from CD4+Th0 and CD8.

1. DOES NOT ARISE from CD4+Th0

b. Controls self-reactive T-cells and suppresses

i. Genes encoding for IL-2

ii. Proliferation of CD4+ and CD8+ T-cells

iii. Antibody production of B-cells

iv. B-cell proliferation

8. A new challenger enters!a. a/i Tregs

i. Made up of CD4+, CD25+, FOXP3+ like nTregs

1. However unlike nTregs these form from Th0 cells, this

means they arise in the periphery outside the thymus.

a. Do this when in the presence of TGFβ alone

i. If it is present with IL-6 or IL-21 it forms

Th17 cells.

ii. Downregulate CD4+ and CD8+ T-cells

9. Other adaptive Tregs

a. Tr1 cells

i. Produce high concentration of IL-10ii. Cytokine profile similar to Th2 cells

iii. Role in peripheral tolerance, perhaps the GI tract

b. Th3 (Tr2) cells

i. Subset of CD4+ regulatory cells that secrete TGFβ

10. Th17 cells

a. Proinflammatory cells, i.e. induce the secretion of inflammatory

mediators.



b. Differentiate when Th0 cells are in the presence of TGFβ and either IL-

6 or IL-21.

i. After differentiating and amplifying the cells are stabilized by

IL-23.

c. Secrete IL-17A, IL-17F, and IL-21.

11. Clinical relevancea. If there is a mutation in FOXP3+ there is going to be an issue with

nTregs. This disease is called IPEX.

i. Results from a mutation in the forkhead box of the P3 gene.

12. Up to this point we have discussed the activation of CD4+ T-cells. Now we go

one and talk about the other T-cells, CD8+ T-cells also known as cytotoxic T-

cells or CTL.

a. CD8+ T-cell activation

i. pCTL interacts with a cell expressing Class I MHC

1. Adhesion molecule CD2 binds with LFA3, LFA-1, and

ICAM (1-3) to stabilize the binding.

ii. Remember antigen is processed by endogenous processing andexpressed with Class I MHC.

iii. Once pCTL binds with Class I MHC it can begin the process of

becoming a full CD8+ cell aka CTL.

1. Requires the presence of IL-2 and IFN γ

a. Comes from Th1 cells.

b. CTL Activity

i. CTL mediated lysis of the target cell is commonly referred to as

delivery of the “lethal hit”. It delivers Perforin to the target.

1. Once it is delivered the CTL detaches and continues

function.

ii. The cell delivered the lethal hit is then destroyed via osmoticlysis or apoptosis.

c. Secondary Immune response

i. After the antigen is eliminated memory cells are left behind

with a specific TCR for that antigen waiting to be reactivated.

13. Superantigen, aka oligoclonal activators

a. Remember cause a cytokine storm by activating a large subset of T-

cells.

14. Gamma and Delta T-cells weren’t really tested. Take it as a for interest

section.

Lecture 9.docx

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