T cells

Question 1

What are the general roles of T cells?

Answer 1

Thymus selected lymphocytes required for cell mediated immunity.

Remove intracellular pathogens by killing infected cells (Tc cells).

Respond to antigenic fragments presented by MHC molecules on APCs.

Costimulation of B cells to enable B cell activation + produce antibodies.

Question 2

What is the T cell repertoire

Answer 2

Th, Tc, and Treg cells.

Question 3

Overview of Helper T cells

Answer 3

Th cells are CD4+.

Recognise antigens presented by MHC class II on APCs.

Th1 migrate to tissues + produce IFN-y to activate macrophages and cytotoxic T cells = pro-inflammatory + destructive

Th2 cells produce IL-4 to activate B cells = antibody promoting

Question 4

What Th cells are implicated in arthritis?

Answer 4

Both Th1 and Th2 cells.

Question 5

Overview of Cytotoxic T cells?

Answer 5

Tc cells are CD8+ and recognise antigen presented on MHC class 1 on HOST cells…

MHC class I is a marker of infection, Tc cells kill virally infected cells.

MHC class I are not expressed on RBC’s

(Overactivity implicated in autoimmunity).

Question 6

Overview of regulatory T cells?

Answer 6

Treg cells are CD4+ and CD25+ and dampen the immune response by secreting IL-10 and TGF-b = anti-inflammatory.

Which activates FoxP3 transcription factor for anti-inflammatory response.

CD25 is IL-2 receptor = which acts as a T cell growth factor.

Depression of Treg cells in cancer and autoimmunity.

Question 7

What is the structure of the T cell receptor?

Answer 7

TCR has a similar structure + assembly to antibodies.

TCR recognises fragment of antigen.

TCR co-stimulatory alpha and beta membrane bound chains with Ig domains…

TCR associated with CD3 signalling chains and invariant chains CD4/CD8, depending on type of T cell.

Undergo thymic selection for self tolerance.
NO SOMATIC HYPERMUTATION, so TCR affinity for antigen is low.

Question 8

Why do TCR’s not undergo somatic hypermutation?

Answer 8

T cells don’t enrich TCR affinity for antigen by somatic hypermutation because having exquisite affinity for antigen is not required. TCR just needs to be sufficiently activated in order to produce cytokines to stimulate other immune cells…

Question 9

What is MHC?

Answer 9

Major Histocompatibility Complex or HLA:

MHC class 1 recognised by CD8+ T cells (Tc cells).

MHC class 1 expressed on all cells except RBCs…

MHC class II recognised by CD4+ T cells.
MHC class II is only expressed on APCs…

MHC defines self - large no. of different alleles - 12 genes are inherited, 3 from each class…

Question 10

What antigens are expressed on MHC class I and class II?

Answer 10

MHC class I express viral antigens on infected cells, except RBCs.

MHC class II express bacterial antigens, mutated proteins (cancer) etc.. on all cells.

Question 11

How are antigens recognised on MHC?

Answer 11

Healtyh cells express self-protein on MHC molecules - which are recognised as self-antigen by T cells.

T cells recognsie small fragments of antigen…

TCR binds across both peptide and MHC residues… whilst CD4/CD8 (of TCR) bind MHC, preventing T cells from killing the APCs.. unless if foreign MHC!

Question 12

What is thymic selection?

Answer 12

Thymic epithelial cells present self-antigen on MHC in the thymus.

During T cell maturation in the thymus, T cells pass over a range of thymic epithelial cells.

T cells which don’t interact with MHC peptide at all = signalled to die by apoptosis = +ve selection.

T cells that bind too strongly + are activated by self-antigen = signalled to die by apoptosis = -ve selection…

Leaving a population of T cells that recognise MHC and self-peptides, but are not activated by it.
= only activated when challenged by foreign antigen on self MHC.

Trophic signals to keep T cells alive, but not enough to undero glonal expansion…

Question 13

What happens to T cells after activation?

Answer 13

naive T cells are challenged by antigen on MHC presented by APCs in the LYMPH NODES (secondary lymphoid organs):

TCR activation + CD3 signalling causes increased size = blast.

Increased rough ER and increased gene transcription - particuarlyly IL-2 and IL-2R (CD25) = IL-2 is a T cell growth factor which stimulates clonal expansion…

Activated Th1 cells migrate to site of infection…
Whilst Th2 cells activate B cells in lymph nodes.

Question 14

What is the role of IL-2?

Answer 14

IL-2 activates IL-2R on T cells (CD25), which is a T cell growth factor = to stimulate clonal expansion of antigen reactive T cells….

Question 15

What co-stimulation is required for T cell activation?

Answer 15

TCR-peptide/MHC activation is not enough for T cell activation…

T cells also require CD28-B7-2 engagement…

CD28 expressed on resting T cells.
B7-2 expressed on resting APCs.

Antigenic engagement of TCR causes CD28 activation.
CD28 can egnage with B7-2 on APC via cell-cell contact.

This CD28-B7-2 engagement leads to upregulation of IL-2 and IL-2R (CD25)
= clonal expansion + cytokine release.

Also, CD-2 and LFA-3 too

Delayed upregulation of CTLA4 on T cell, and B7-1 on APC (inhibitory engagement)

Question 16

How can co-stimulatory molecules dampen down T cell responses?

Answer 16

CD28-B7-2 engagement leads to upregulation of IL-2, but also delayed upregulation of CTLA4 on T cells and B7-1 on APCs.

CTLA-4 binds to B7-1 on APCs, causing downregulation of CD28 signalling.

Question 17

What are the responses of Th1 cells and IFN-y?

Answer 17

Th1 cells migrate to site of infection, release IFN-y to activate macrophages.

Stimulate bone marrow production of monocytes, which in tissue mature to macrophages.

IFN-y leads to increased adhesion molecule expression on endothelium and induce chemokine release= increased leukocyte migration.

= ACUTE inflammation

Question 18

What are the responses of Cytotoxic T cells?

Answer 18

Antigen presentation via MHC class I + costimulation

= Perforin dependent killing or Fas-dependent killing of infected cell:

Perforin secretion creates holes in infected cell PM, TC cell secretes granzyme, which invade + activate pro-caspases = triggering apoptosis.

Tc cells express Fas ligand - binding to Fas receptor on infected cell = activating intracellular caspases in infected cell.

Question 19

What was TGN1412?

Answer 19

TGN1412 was a humanised monoclonal antibody CD28 agonist.

CD28 = expressed on T cells for co-stimulation by APC B7-2…

Designed for B cell chronic leukeamia + RA.

CD28 activation in absenec of TCR engagement thought to induce Treg cells and anti-inflammatory cytokines, but instead caused cytokine storm!!!

Question 20

How are MHC class I prepared and loaded?

Answer 20

Both MHC classes can bind a variety of peptides via peptide backbone, with large sequence independence.

MHC class 1 expressed on all cells, except RBCs.

MHC load small peptides around 8 AAs long.

Antigenic peptide fragments are derrived from proetolysis…

Peptide is loaded onto the MHC class I in the Endoplasmic reticulum = in order for correct MHC folding..

Question 21

How are MHC class II prepared and loaded?

Answer 21

MHC class II are expressed only on professional APCs… like B cells, macrophages, neutrophils, dendritic cells.

MHC class II load larger antigens - peptides around 13-17 AAs long…

Antigen is degraded by proteolysis in endosomes + lysosomes.

MHC is preassembled bound with invariant chain until it reaches the endosome - to prevent binding self-peptides on the way…

The invariant chain is replaced by antigenic peptide from endosome and the complex translocates to the surface.