[M4] Topic 2: T Lymphocyte Activation and Differentiation

What is the initiating event of adaptive immunity?

The interaction between a naïve T cell and an antigen-presenting cell (APC).

What system is alerted before adaptive immunity is initiated?

The innate immune system.

How is the innate immune system alerted to infection or damage?

Through pattern recognition receptors (PRRs).

How are APCs activated?

By recognizing pathogens or damage via PRRs.

What are two ways APCs acquire antigens?

By engulfing a pathogen or becoming infected themselves.

What do APCs do after activation?

They process and present pathogenic peptides in MHC class I or class II molecules.

Where do activated APCs migrate after encountering a pathogen?

To secondary lymphoid tissues such as draining lymph nodes, spleen, or mucosa-associated lymphoid tissue (MALT).

Where do T cells develop and generate unique, random T cell receptors?

In the thymus.

What types of selection do T cells undergo in the thymus?

Positive selection (MHC restriction) and negative selection (self-tolerance).

What type of T cells enter circulation after thymic development?

Mature, naïve, lineage-committed T cells (either CD4 or CD8).

How many signals are required to activate a T cell?

Two signals.

What is the first signal required for T cell activation?

TCR engagement with peptide-MHC complex.

What is the second signal required for T cell activation?

Costimulatory molecule interaction.

What happens to T cells once they are activated?

They differentiate into effector and memory cells.

What are costimulatory signals required for in T cells?

Optimal activation and proliferation.

What is Signal 1 in T cell activation?

TCR binding to antigen-MHC complex.

What is Signal 2 in T cell activation?

Costimulatory molecule interaction (e.g., CD28 on T cell binding to B7 on APC).

What is Signal 3 in T cell activation?

Cytokine signaling that directs T cell differentiation and response.

What kinase is activated at the beginning of TCR signaling?

Lck (a tyrosine kinase)

What stabilizes the interaction between TCR and MHC-peptide on the APC?

The coreceptor CD4 or CD8

What role do the cytoplasmic tails of CD4 and CD8 play?

They guide Lck to the TCR-MHC complex

What does Lck phosphorylate during TCR signaling?

ITAMs (Immunoreceptor Tyrosine-based Activation Motifs) on CD3

What happens to phosphorylated ITAMs?

They become docking sites for other signaling proteins

What is the end result of TCR signaling cascades?

Activation of transcription factors and their translocation into the nucleus

What is required in addition to TCR engagement for successful activation of naïve T cells?

Engagement of costimulatory molecules like CD28

Why are costimulatory signals important?

They are required for T cell activation and proliferation

What type of receptors facilitate T cell activation?

Positive costimulatory receptors

What is the role of CD28 in T cell activation?

It is involved in initial activation, enhances TCR-induced proliferation and survival

What does CD28 bind to on APCs?

CD80 or CD86

What is ICOS and when is it expressed?

Inducible costimulator, expressed on memory and effector T cells

What does ICOS bind to?

ICOSL (ICOS-Ligand) on activated APCs

What is the function of ICOS?

It may help maintain activity of differentiated T cells

What type of receptors help turn off T cell activation?

Negative costimulatory receptors

What is CTLA-4 and when is it induced?

A negative costimulatory receptor, induced 24 hours after activation, peaks 2-3 days post-stimulation

What does CTLA-4 bind to, and how does it affect T cell signaling?

Binds CD80/CD86 with higher affinity than CD28 and shuts down signaling pathways

What is PD-1 and its role in immunity?

A receptor that helps mediate T-cell tolerance in nonlymphoid tissues

What does PD-1 bind to?

PD-L1 or PD-L2

Where does activation of a naïve T cell occur?

In secondary lymphoid tissues

What does activation of a naïve T cell lead to?

Generation of effector and memory T cells

When are naïve T cells activated?

When they simultaneously engage MHC-peptide complexes and costimulatory ligands on APCs

What shapes the outcome of T cell activation?

Cytokines produced by APCs

How do cytokines influence T cell activation?

They determine the type of effector T cell the naïve T cell will become

What does it mean when a cytokine is pleiotropic?

It induces different biological effects depending on the target cell.

What does it mean when cytokines are redundant?

They mediate similar effects on the target cell.

What is the synergy effect in cytokine activity?

The combined activity of two cytokines is greater than the sum of their individual effects.

What is an antagonistic effect between cytokines?

One cytokine inhibits the effect of another.

What is a cytokine cascade effect?

One cytokine acts on a target cell to produce additional cytokines.

What type of cytokine is IL-2?

An autocrine cytokine.

What do T cells produce upon activation?

IL-2 and the IL-2 receptor (IL-2R).

What happens when IL-2 binds to its receptor?

It induces a strong proliferation signal in the T cell.

What is the function of polarizing cytokines?

They direct the developing T cell down specific subset development pathways.

What happens to a naïve T cell after successful engagement with an APC?

It becomes activated and undergoes repeated rounds of cell division.

What do initial activation signals (1 and 2) induce in T cells?

Upregulation of pro-survival genes like Bcl-2

Transcription of IL-2 and IL-2R (CD25)

Proliferation of memory and effector T cells

What regulates the differentiation of CD4+ T helper cell subsets?

Polarizing cytokines.

What determines which polarizing cytokines are produced by APCs?

The PRRs engaged by PAMPs or DAMPs during antigen recognition.

What happens when different PRRs are engaged by different antigens?

Different cytokines are produced, guiding T cell differentiation.

What are cytokines?

Proteins that communicate among cells of the immune system.

How do cytokines signal cells?

By binding noncovalently to high-affinity, complementary cell-bound receptors.

What is the effect of cytokine signaling on target cells?

It changes the cell's transcriptional program and functional state.

What does a cytokine signal typically instruct a cell to do?

Change its metabolic activity, proliferation, or effector cytokine production.

What happens after cytokine binding to its receptor?

Receptor dimerization occurs.

What is activated following receptor dimerization?

JAK tyrosine kinases via auto-phosphorylation.

What do JAKs phosphorylate?

STAT transcription factors.

What do phosphorylated STATs do?

Dimerize and translocate to the nucleus to activate specific genes.

What is the first property that distinguishes T helper subsets?

Distinct polarizing cytokines that induce the expression of a master gene regulator.

What is the second property that distinguishes T helper subsets?

A master gene regulator that controls the expression of effector cytokines.

What is the third property that distinguishes T helper subsets?

A signature set of effector cytokines produced by the cell.

What polarizing cytokines promote Treg differentiation?

IL-2, TGF-β

What is the master transcriptional regulator for Treg cells?

FoxP3

What effector cytokines do Treg cells produce?

IL-10, TGF-β

What is the function of Treg cells?

Suppresses immune responses

What is Treg role in disease?

Inhibits antitumor response

What polarizing cytokines promote Th17 differentiation?

IL-6, IL-23, TGF-β

What is the master transcriptional regulator for Th17 cells?

RORγt

What effector cytokines do Th17 cells produce?

IL-17A, IL-17F, IL-22

What is the function of Th17 cells?

Combats extracellular pathogens (bacteria, fungi) in barrier tissues

What is Th17 role in disease?

Autoimmunity, tissue inflammation

What polarizing cytokine promotes Th2 differentiation?

IL-4

What is the master transcriptional regulator for Th2 cells?

GATA3

What effector cytokines do Th2 cells produce?

IL-4, IL-5, IL-13

What is the function of Th2 cells?

Combats helminth infection, activates eosinophils

What is Th2 role in disease?

Allergy

What polarizing cytokines promote Tfh differentiation?

IL-6, IL-21

What is the master transcriptional regulator for Tfh cells?

Bcl-6

What is the function of Tfh cells?

Regulates affinity maturation of germinal center B cells

What is Tfh role in disease?

Autoimmunity

What polarizing cytokines promote Th1 differentiation?

IL-12, IFN-γ, IL-18

What is the master transcriptional regulator for Th1 cells?

T-bet

What effector cytokines do Th1 cells produce?

IFN-γ, TNF

What is the function of Th1 cells?

Combats intracellular pathogens, activates macrophages

What is their role in disease?

Tissue inflammation

What do Th1 cells regulate immunity against?

Intracellular bacteria and viruses

What do Th2 cells regulate immunity against?

Extracellular parasitic infections

What other role are Th2 cells involved in?

Allergy

What do Th17 cells regulate immunity against?

Extracellular bacteria and fungi

What condition can Th17 cells contribute to?

Autoimmunity

What do Treg cells do?

Inhibit immune responses and help terminate immune reactions

What role do Treg cells play in autoimmunity?

They help inhibit it

What do Tfh cells do?

Regulate humoral immunity by helping B cells

What do T helper cells help B cells become?

High-affinity, long-lived plasma cells