T Lymphocytes Flashcards
What are the basic characteristics of TCR?
- Are membrane receptors & not secreted
- Responsible for specific Ag recognition in the adaptive immune system
- Distinguish & bind to a large number of Ags
What is the structure of TCR?
- Consist of alpha and beta chain, recognize Ag
- Each chain contains a V and C region
- TCR Complex = TCR + CD3 complex
- TCR cytoplasmic tails are too short hence require CD3 for signal transduction (CD3 chains have long cytoplasmic tails)
What is the purpose of VDJ recombination?
Different VDJ combinations result in different specificities, allowing lymphocyte diversity
CD4 T cells recognize what class of MHC?
Class II
CD8 T cells recognize what class of MHC?
Class I
What is TCR binding specific for?
Peptide and MHC
How many kinds of peptide-MHC complexes on APC are T cells specific for?
1 - Monogamy relationship
Define the functions of the key accessory molecules of T lymphocytes and their corresponding ligands.
What is a T cell accessory molecule?
Participates in Ag responses but are not the receptors for Ag
What is the function of CD3?
Signal transduction by TCR complex
What is the function of CD4?
Signal transduction
What is the ligand for CD4 and where is the ligand expressed on?
Class II MHC
Expressed on APCs
What is the function of CD8?
Signal transduction
What is the ligand for CD8 and where is it expressed on?
Class I MHC
Expressed on APCs, CTL target cells
What is the function of CD28?
Costimulation of naive T cells
What is the ligand for CD28 and where is it expressed on?
B7-1/B7-2
Expressed on APCs
*What is the function of CTLA-4?
Negative regulator of T cell activation
What is the ligand for CTLA-4 and where is it expressed on?
B7-1/B7-2
Expressed on APCs
What is the function of CD-2?
Signal transduction & ADHESION
What is the ligand for CD-2 and where is it expressed on?
LFA-3
Hematopoietic & non-hematopoietic cells
What is the function of LFA-1?
Adhesion
What is the ligand for LFA-1 and where is it expressed on?
ICAM-1
APCs, Endothelium
What is the function of VLA-4?
Adhesion
What is the ligand for VLA-4 and where is it expressed on?
VCAM-1 and fibronectin
Endothelium
Where are the co-stimulators in T cell activation found?
APC surface
What is the function of costimulators?
Provides stimulus (2nd signal) for activation of naive T cells, in addition to Ag recognition (1st) signal)
What are the co-stimulators in T cell activation?
B7-1 (CD80) and B7-2 (CD86) molecules:
1. Best defined co-stimulator on APC
2. Bind to CD28 (expressed on all T cells)
Can resting APCs activate naive T cells?
No
When are cytokines produced? What is the function of cytokines?
Produced during innate immune responses to microbes and induces expression of co-stimulator on APC
*What is the co-stimulation requirement?
Ensures that naive T cells are activated fully by microbial Ag, not by harmless substances
What does CD40 ligand bind to?
CD40 ligand (CD40L) binds to CD40 on APC
What happens when CD40L (CD154) binds to CD40?
APC expresses more B7 co-stimulator & secretes cytokines (ex. IL-2) that enhance T cell differentiation.
CD40L-CD40 interaction allows APC to better stimulate T cells
What is required for the sustained expression of CD40L?
B7-CD28 as well as Ag
B7 and CD40 pathways stimulate each other
What is the clinical relevance of costimulation?
- RA Therapy - blocks B7:CD28 unwanted response
- Abs blocking CD40:CD40L - reduce/prevent graft rejection in transplant recipients
- Tumour therapy - enhances co-stimulator expression
- CTLA-4 is induced in activated T cells and binds B7 on APC which is critical for limiting & terminating immune responses
- a deletion in the gene will result in excessive lymphocyte expansion & autoimmune disease
What is the first signal in T cell activation?
Ag recognition by TCR
What is the second signal in T cell activation?
Interactions of T cell accessory molecules with their ligands on APC
What determines the outcome of T cell activation?
Duration and affinity of TCR-Ag interaction
What are the different subsets of T cells and what kind of effector cells do they differentiate into? State the functions of these effector cells.
Naive CD4 becomes T helper cell (Th cell)
- Produce cytokines
- Promote Ab production (HUMORAL IMMUNITY) or macrophage killing of ingested microbes (CELL MEDIATED IMMUNITY)
Naive CD8 becomes cytotoxic T-lymphocyte (CTL)
- Directly kill cells harboring microbes (virus/bacteria) in the cell cytoplasm
How does cytotoxic T lymphocytes cause a cell to undergo apoptosis?
- Requires contact with target cell
- Deliver PERFORIN and GRANZYME B into the target cll
- Granzyme B triggers an enzymatic chain reaction inside the target cell that causes the cell to commit suicide by apoptosis
What does T helper 17 (Th17) secrete?
IL-17 as key cytokine
What are the effector functions of Th17?
- Host defence against some bacteria and fungal infections
- Promote recruitment of neutrophils & monocytes
Where do regulatory T cells develop? What are their functions?
Develop in the thymus (major) or peripheral lymphoid organs
Functions:
1. Block activation of potentially harmful lymphocytes specific for self Ags
2. Control autoimmunity, allergic & inflammatory reactions and responses to infectious agents and tumors
Is the development of T cell subsets a random process? What is it regulated by?
- Development of Th1, Th2, Th17 and Tregulatory subsets is NOT a random process
- Regulated by the stimuli that naive CD4+ T cells receive when encountering microbial Ag (via initial innate response)
What is the development stimulus for the different T cell subsets?
Th1 - IL-12 & IFN-gamma
Th2 - IL4
Th17 - IL-6, IL-1beta, IL-23, TGF-beta
Tregulatory - IL-2 & TGF-beta
What are the cytokines produced by the different T cell subsets?
Th1 - IFN-gamma
Th2 - IL4
Th17 - IL-17 & IL-22
Tregulatory - IL-10 & TGF-beta
What are the effector functions of the different T cell subtypes?
Th1
- Host defence against intracellular microbes
- Inflammation
Th2
- Defend against extracellular microbes
- Stimulate B cells
Th17
- Host defence against infections
- In tissue inflammation during autoimmunity: MS, RA, IBD
Tregulatory
- maintenance of self-tolerance
What happens after infection is cleared?
- Proliferated cells are deprived of survival signals (Ag, CD28, IL-2)
- Cells die by apoptosis
- T cell response subsides within 1-2 weeks
- Only surviving memory lymphocytes remain
What does CTLA-4 stand for?
cytotoxic T-lymphocyte associated protein 4
Which has higher affinity for B7-1 and B7-2, CTLA-4 or CD28?
CTLA-4
What does Ipilimumab do?
Blocks CTLA-4 for unresectable/metastatic melanoma
