T Regulators and T cell exhaustion

Explain this picture

Interaction	Effect
TCR ↔ antigen-MHC	🟢 Recognizes target / initiates activation
CD28 ↔ B7	🟢 Accelerator (co-stimulation)
CTLA-4 ↔ B7	🔴 Early brake
PD-1 ↔ PD-L1	🔴 Later brake

‘X’ is the checkpoint inhibition therapeutically

What are the 2 ways of T cell tolerance

1. Regulatory T cells
2. T cell Exhaustion

Why T cell tolerance is required physiologically

There are a wide rande of T cell receptors through random rearrangement of TCR gene segments. This leads to tcr recognising wide range of antigens. But this also means sometimes due to the tcr genetic diversity, it will also end up recognising normal protein as an antigen. Hence to prevent autoimmunity, T cell tolerance is required.

TCR diversity → self-reactivity is unavoidable → tolerance is required.

Why FOXP3 deficiency is significant?

FOXP3 is a transcription factor for Tregs. Deficiency of FOXP3 causes defective/absent functional Tregs → uncontrolled immune activation → severe inflammatory disease. Known as IPEX syndrome.

Where do Tregs come from and how are they generated

Thymic Tregs (tTregs) — generated during T-cell development in the thymus.

Peripheral Tregs (pTregs) — conventional mature CD4 T cells that acquire the Treg phenotype in peripheral tissues.

During thymic t cell developement- 3 outcomes are possible- generate strong self reactive t cells / intermediate self reactive t cells / weak self reactive t cells. predict the outcome of each

strong self reactive t cells- negative selection- destroyed intermediate self reactive t cells- T REGS

weak self reactive t cells- T Cells

What are tregs good for

Explain this graph

low Tregs → better progression-free survival

high Tregs → worse progression-free survival

Even when we engineer clever ways of making T cells recognize cancer, immune suppression in the patient/tumor environment can still limit the response. Explain

1. Car-T therapy - Tregs interfere

2. Bite therapy- Functionally brings T cells to tumour antigen and helps in killing tumour cells. Tregs puts a brake on the T cell and it becomes ineffective at killing tumour cells.

what tells the immune system whether an antigen should cause tolerance or killing?

TCR cannot by itself tell if an antigen is self reactive or pathogenic. Hence it required INFLAMMATION/COSTIMULATION.

There is insufficient inflammation in tumour cells due to insuffienct IFN (inflammatoroy signalling).

How does tumour microenvironment perform immunosuppression

It favors development/maintenance of a regulatory phenotype (It converts t cells to tregs) due to its environment-

low O₂
low glucose
IL-35
TGF-β

Treg abundance increases with tumor stage. Explain

more tumor Tregs → more immune suppression → less effective antitumor immunity

Why Identifying Tregs is difficult (we have FOXP3 to identify Tregs).

How can the same FOXP3 gene can be used to idetify tregs from t cells

Because FOXP3 expression alone does not always identify a bona fide Treg- it is expressed by other cells too. So there is no clear biomarker for treg.

Mehylating foxp3 gene

Treg functions in relation to these cells for cancer promotion

Tregs inhibit Tconv via APCs through 4 mechanisms. Explain

1. IL-2 “stealing” — cytokine competition

Tconv activation → Tconv produces IL-2 → Tregs express lots of CD25 (increases affinity to IL2) → Tregs capture IL-2 → less IL-2 available to Tconv → reduced Tconv survival/proliferation because of decreased inflammation → suppression

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2. CTLA-4 — reducing APC costimulation

Treg expresses high CTLA-4 → CTLA-4 binds B7 (CD80/CD86) on APC → B7 is removed/reduced from APC → less B7 available to bind CD28 on Tconv → ↓ costimulation → ↓ Tconv activation

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3. Suppressive cytokines + adenosine

Treg → releases IL-10, IL-35 & TGF-β + generates adenosine via CD39/CD73 → locally immunosuppressive environment.

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4. Tissue repair / growth factors

Treg → stimulates tissue/epithelial repair and growth → tumor progression

Tregs can block two major stages- what are they

T-cell priming in lymphoid organs

Effector T-cell function within the tumor microenvironment.

Causes of T cell exhaustion

Why doesn't anti-PD-1 cure everyone?

Exhausted cells can express multiple inhibitory receptors.Therefore blocking only one inhibitory pathway may not completely reverse the cellular state.

Exhaustion is a multistage process. Explain. In which stage does inhibiting PD1 work

different methods to combat T cell exhaustion

TIL therapy

Degradable CAR-T cells (alllows periodic resting of t cells)

Preventing CAR T cell exhaustion by genetic modification