Learning about T cells

Last updated: 2026-03-25

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File	Version	Author	Date	Message
Rmd	993148d	Dave Tang	2026-03-25	Learning about T cells

Notes inspired by the landmark study: Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system (Zinkernagel and Doherty, 1974).

This study demonstrated that cytotoxic T cells can only kill virus-infected target cells that share the same major histocompatibility complex (MHC) alleles, establishing the concept of MHC restriction. This discovery was awarded the Nobel Prize in Physiology or Medicine in 1996.

Basics

T cells (T lymphocytes) are a type of white blood cell that plays a central role in adaptive immunity.
The “T” stands for thymus, the organ where T cells mature.
Unlike B cells, which produce soluble antibodies, T cells mediate their effects through direct cell-cell contact or by secreting cytokines.
T cells recognise antigen fragments (peptides) presented on the surface of other cells by MHC molecules, rather than recognising free antigen directly.

T cell receptor (TCR)

TCR structure

The T cell receptor is a heterodimeric cell-surface protein responsible for antigen recognition. There are two forms:

$\alpha\beta$ TCR: Composed of an $\alpha$ chain and a $\beta$ chain. Found on the vast majority (~95%) of T cells. Recognises peptide antigens presented by MHC molecules.
$\gamma\delta$ TCR: Composed of a $\gamma$ chain and a $\delta$ chain. Found on a minor population (~5%) of T cells. Can recognise non-peptide antigens (e.g., phosphoantigens, lipids) without MHC restriction.

Each TCR chain consists of:

Variable (V) region: Contains the antigen-binding site. Analogous to antibody variable domains.
Constant (C) region: Anchors the receptor and connects to the signalling complex.
Transmembrane region: A single-pass transmembrane domain.

Unlike antibodies, the TCR is always membrane-bound and is never secreted. Each T cell expresses a single TCR specificity (allelic exclusion).

CD3 signalling complex

The TCR itself has very short cytoplasmic tails and cannot signal on its own. It associates with the CD3 complex, which consists of:

CD3$\epsilon\gamma$ heterodimer
CD3$\epsilon\delta$ heterodimer
CD3$\zeta\zeta$ ($\zeta$-chain) homodimer

The CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domains. The $\zeta$-chain homodimer alone contributes 6 ITAMs. Upon TCR engagement, ITAMs are phosphorylated by the Src family kinase Lck, initiating downstream signalling.

Comparison with antibodies

Feature	TCR	Antibody (BCR)
Chains	$\alpha\beta$ or $\gamma\delta$	Heavy + light
Antigen form	Peptide-MHC complex	Native antigen (any shape)
Secreted form	No	Yes (immunoglobulins)
Somatic hypermutation	No	Yes
Valency	Monovalent	Bivalent (or higher for IgM)
Isotype switching	No	Yes
Diversity mechanism	V(D)J recombination	V(D)J + SHM

TCR diversity

TCR diversity is generated through V(D)J recombination, the same mechanism used by B cells for antibody diversity:

$\beta$ chain: V, D, and J segments (similar to antibody heavy chain)
$\alpha$ chain: V and J segments only (similar to antibody light chain)

The estimated diversity of the $\alpha\beta$ TCR repertoire is >10^15, driven largely by:

Combinatorial diversity (random segment selection)
Junctional diversity (N- and P-nucleotide additions at junctions)
$\alpha\beta$ chain pairing

Critically, unlike antibodies, TCRs do not undergo somatic hypermutation. TCR affinity for antigen is therefore fixed after thymic selection.

MHC restriction and antigen presentation

MHC molecules

Major histocompatibility complex (MHC) molecules present peptide fragments on the cell surface for T cell recognition. In humans, MHC is called HLA (human leukocyte antigen).

Feature	MHC class I	MHC class II
Genes (human)	HLA-A, HLA-B, HLA-C	HLA-DP, HLA-DQ, HLA-DR
Structure	$\alpha$ chain + $\beta_2$-microglobulin	$\alpha$ chain + $\beta$ chain
Expression	All nucleated cells	Professional APCs (dendritic cells, macrophages, B cells)
Peptide source	Intracellular (cytosolic)	Extracellular (endosomal)
Peptide length	8-10 amino acids	13-25 amino acids
Recognised by	CD8+ T cells	CD4+ T cells
Binding groove	Closed ends	Open ends

Antigen processing pathways

MHC class I pathway (endogenous/cytosolic):

Intracellular proteins (including viral proteins) are degraded by the proteasome.
Peptide fragments are transported into the endoplasmic reticulum (ER) by the TAP transporter (transporter associated with antigen processing).
Peptides are loaded onto MHC class I molecules with the help of chaperones (calnexin, calreticulin, tapasin, ERp57).
Peptide-MHC I complexes are transported to the cell surface.
Recognised by CD8+ cytotoxic T cells.

MHC class II pathway (exogenous/endosomal):

Extracellular antigens are internalised by endocytosis or phagocytosis.
Antigens are degraded in acidified endosomal/lysosomal compartments.
MHC class II molecules are synthesised in the ER with invariant chain (Ii/CD74) blocking the peptide groove.
In the endosome, invariant chain is degraded, leaving the CLIP fragment (class II-associated invariant chain peptide).
HLA-DM catalyses exchange of CLIP for antigenic peptide.
Peptide-MHC II complexes are transported to the cell surface.
Recognised by CD4+ helper T cells.

Cross-presentation: Dendritic cells can present exogenous antigens on MHC class I molecules, enabling CD8+ T cell responses to extracellular pathogens and tumour antigens. This is critical for anti-tumour immunity and vaccination.

T cell development

T cell precursors originate in the bone marrow and migrate to the thymus for maturation. Thymic development involves several stages:

Double-negative (DN) stage

Thymocytes initially express neither CD4 nor CD8 (CD4$^-$CD8$^-$). The DN stage is subdivided based on CD44 and CD25 expression:

Stage	CD44	CD25	Key events
DN1	+	-	Thymic entry, Notch signalling
DN2	+	+	TCR $\beta$ gene rearrangement begins
DN3	-	+	$\beta$-selection checkpoint
DN4	-	-	Proliferation

$\beta$-selection: At DN3, a productive TCR $\beta$ chain rearrangement is tested by pairing with a surrogate pre-T$\alpha$ chain. Successful $\beta$-selection triggers proliferation and progression to the double-positive stage.

Double-positive (DP) stage

Thymocytes express both CD4 and CD8 (CD4$^+$CD8$^+$). The TCR $\alpha$ chain is rearranged, generating a complete $\alpha\beta$ TCR. Two critical selection events follow:

Positive selection (thymic cortex):

DP thymocytes interact with cortical thymic epithelial cells (cTECs) presenting self-peptides on MHC.
Thymocytes whose TCR binds self-MHC with moderate affinity receive survival signals.
Thymocytes that fail to recognise self-MHC die by neglect (~90% of DP thymocytes).
MHC class I recognition leads to CD8 lineage commitment; MHC class II recognition leads to CD4 lineage.

Negative selection (thymic cortex and medulla):

Thymocytes whose TCR binds self-peptide-MHC with high affinity are eliminated by apoptosis (clonal deletion).
Medullary thymic epithelial cells (mTECs) express the transcription factor AIRE (autoimmune regulator), which drives expression of tissue-restricted self-antigens in the thymus.
This process establishes central tolerance, eliminating most self-reactive T cells.
Some self-reactive CD4+ T cells are diverted to become regulatory T cells (Tregs) instead of being deleted.

Single-positive (SP) stage

Mature thymocytes express either CD4 or CD8 and exit the thymus as naive T cells into the peripheral circulation.

Major T cell subsets

CD4+ helper T cells

CD4+ T cells recognise peptide-MHC class II complexes and orchestrate immune responses by secreting cytokines. Upon activation, naive CD4+ T cells differentiate into specialised subsets:

Subset	Key transcription factor	Signature cytokines	Primary function
Th1	T-bet	IFN-$\gamma$, TNF-$\alpha$	Intracellular pathogens, macrophage activation
Th2	GATA-3	IL-4, IL-5, IL-13	Helminth defence, allergic responses
Th17	ROR$\gamma$t	IL-17A, IL-17F, IL-22	Extracellular bacteria, fungi, mucosal defence
Tfh	Bcl-6	IL-21, IL-4	B cell help in germinal centres
Treg	FoxP3	IL-10, TGF-$\beta$	Immune suppression, self-tolerance
Th9	PU.1	IL-9	Anti-helminth, allergic inflammation
Th22	AHR	IL-22	Epithelial barrier function

Subset differentiation is driven by the cytokine milieu at the time of T cell activation. Plasticity between subsets has been observed, particularly under inflammatory conditions.

CD8+ cytotoxic T cells (CTLs)

CD8+ T cells recognise peptide-MHC class I complexes and directly kill target cells (virus-infected cells, tumour cells). Killing mechanisms include:

Perforin/granzyme pathway: Perforin forms pores in the target cell membrane; granzymes (serine proteases) enter through the pores and activate caspases, triggering apoptosis.
Fas/FasL pathway: FasL (CD95L) on the CTL engages Fas (CD95) on the target cell, activating the extrinsic apoptosis pathway.
Cytokine secretion: TNF-$\alpha$ and IFN-$\gamma$ contribute to anti-viral and anti-tumour responses.

After pathogen clearance, most effector CD8+ T cells die by apoptosis (contraction phase), but a subset survives as memory T cells.

Memory T cells

Memory T cells provide rapid and enhanced responses upon re-encountering the same antigen. Key subsets:

Central memory T cells (T$_{CM}$): Express CCR7 and CD62L. Reside in secondary lymphoid organs. Proliferate rapidly upon restimulation.
Effector memory T cells (T$_{EM}$): Lack CCR7 and CD62L. Circulate through peripheral tissues. Provide immediate effector function.
Tissue-resident memory T cells (T$_{RM}$): Permanently reside in peripheral tissues (skin, lung, gut) without recirculating. Express CD69 and CD103. Provide frontline defence at barrier sites.
Stem cell memory T cells (T$_{SCM}$): Express CD95, CD122, and naive markers (CCR7, CD62L, CD45RA). Self-renewing with multipotent capacity.

$\gamma\delta$ T cells

$\gamma\delta$ T cells represent ~5% of peripheral blood T cells but are enriched at mucosal surfaces (skin, gut, lung). Key features:

Recognise non-peptide antigens (phosphoantigens, lipids) without classical MHC restriction.
Bridge innate and adaptive immunity with rapid effector responses.
Can perform cytotoxicity, cytokine production, and antigen presentation.
V$$9V$$2 T cells are the predominant subset in human blood and recognise microbial and endogenous phosphoantigens.

Other specialised T cell populations

NKT cells (natural killer T cells): Recognise lipid antigens presented by the MHC class I-like molecule CD1d. Express a semi-invariant TCR (V$$24-J$$18 in humans). Rapidly produce large amounts of cytokines (IFN-$$, IL-4) upon activation.
MAIT cells (mucosal-associated invariant T cells): Recognise microbial vitamin B metabolites presented by MR1 (MHC-related protein 1). Express a semi-invariant TCR (V$$7.2-J$$33 in humans). Abundant in human blood, liver, and mucosal tissues.

T cell activation

Naive T cell activation requires three signals:

Signal 1: TCR engagement

The TCR recognises a specific peptide-MHC complex on an antigen-presenting cell (APC). The co-receptors CD4 or CD8 bind to conserved regions of MHC class II or class I, respectively, stabilising the interaction and bringing the kinase Lck into proximity with CD3 ITAMs.

Key downstream signalling events:

Lck phosphorylates CD3 ITAMs.
ZAP-70 is recruited and activated.
ZAP-70 phosphorylates LAT and SLP-76, forming a signalosome.
Three major pathways are activated:
- PLC$$1 $\rightarrow$ DAG + IP3 $\rightarrow$ NF-$\kappa$B and NFAT activation
- Ras/MAPK $\rightarrow$ AP-1 activation
- PI3K/Akt $\rightarrow$ cell survival and metabolism

Signal 2: Co-stimulation

Co-stimulatory signals are required to prevent T cell anergy (functional unresponsiveness). Key co-stimulatory and co-inhibitory molecules:

Molecule	Ligand	Effect	Expression
CD28	CD80 (B7-1), CD86 (B7-2)	Co-stimulation	Constitutive on naive T cells
CTLA-4	CD80, CD86	Co-inhibition	Upregulated after activation
PD-1	PD-L1 (B7-H1), PD-L2 (B7-DC)	Co-inhibition	Upregulated after activation
ICOS	ICOS-L	Co-stimulation	Upregulated after activation
4-1BB (CD137)	4-1BBL	Co-stimulation	Upregulated after activation
OX40 (CD134)	OX40L	Co-stimulation	Upregulated after activation
LAG-3	MHC class II	Co-inhibition	Upregulated after activation
TIM-3	Galectin-9, CEACAM1	Co-inhibition	Upregulated after activation
TIGIT	CD155, CD112	Co-inhibition	Upregulated after activation

TCR engagement without co-stimulation (Signal 1 alone) leads to anergy or deletion, a mechanism of peripheral tolerance.

Signal 3: Cytokines

Cytokines produced by APCs and surrounding cells direct the differentiation programme of activated T cells. For example:

IL-12 + IFN-$\gamma$ $\rightarrow$ Th1 differentiation
IL-4 $\rightarrow$ Th2 differentiation
TGF-$\beta$ + IL-6 $\rightarrow$ Th17 differentiation
TGF-$\beta$ + IL-2 $\rightarrow$ Treg differentiation
IL-12 + IL-2 $\rightarrow$ CTL effector differentiation

T cell exhaustion

Chronic antigen stimulation (persistent viral infections, cancer) drives T cells into a dysfunctional state called exhaustion. Exhausted T cells are characterised by:

Progressive loss of effector functions (IL-2 production lost first, then TNF-$\alpha$, then IFN-$\gamma$)
Sustained expression of multiple inhibitory receptors (PD-1, LAG-3, TIM-3, CTLA-4, TIGIT)
Altered transcriptional programme driven by TOX and other transcription factors
Epigenetic remodelling that distinguishes exhaustion from normal effector or memory states
Reduced proliferative capacity and cytotoxicity
Metabolic shift from oxidative phosphorylation to dysfunctional states

T cell exhaustion is a major barrier to effective anti-tumour immunity and is the target of immune checkpoint blockade therapies.

Key surface markers

Common markers used to identify T cell populations by flow cytometry or single-cell RNA sequencing:

Marker	Expression	Function
CD3	All T cells	TCR signalling complex
CD4	Helper T cells	MHC class II co-receptor
CD8	Cytotoxic T cells	MHC class I co-receptor
CD45RA	Naive and T$_{EMRA}$ cells	Phosphatase isoform
CD45RO	Memory T cells	Phosphatase isoform
CCR7	Naive and T$_{CM}$ cells	Lymph node homing
CD62L	Naive and T$_{CM}$ cells	Lymph node homing
CD69	Recently activated, T$_{RM}$ cells	Tissue retention
CD25	Activated T cells, Tregs	IL-2 receptor $\alpha$ chain
FoxP3	Tregs	Lineage transcription factor
PD-1	Activated/exhausted T cells	Inhibitory receptor
Ki-67	Proliferating cells	Proliferation marker

T cell-based immunotherapies

Immune checkpoint inhibitors

Blocking co-inhibitory receptors can reinvigorate exhausted T cells in the tumour microenvironment:

Anti-CTLA-4 (ipilimumab): Blocks CTLA-4, enhancing T cell activation and depleting intratumoral Tregs. First checkpoint inhibitor approved (melanoma, 2011).
Anti-PD-1 (nivolumab, pembrolizumab): Blocks PD-1, restoring effector function in exhausted T cells. Broadly effective across many cancer types.
Anti-PD-L1 (atezolizumab, durvalumab): Blocks PD-L1 on tumour cells and APCs.
Combination therapies: Anti-CTLA-4 + anti-PD-1 combinations show improved responses in several cancers (e.g., melanoma, renal cell carcinoma).

The discovery of cancer therapy by inhibition of negative immune regulation was awarded the Nobel Prize in Physiology or Medicine in 2018 to James Allison (CTLA-4) and Tasuku Honjo (PD-1).

CAR-T cell therapy

Chimeric antigen receptor (CAR) T cells are engineered T cells that express a synthetic receptor combining:

An extracellular single-chain variable fragment (scFv) derived from an antibody, providing antigen recognition.
A hinge and transmembrane domain for membrane anchoring.
Intracellular signalling domains for T cell activation.

CAR generations differ in their intracellular signalling domains:

Generation	Signalling domains	Features
1st	CD3$\zeta$ only	Poor persistence and expansion
2nd	CD3$\zeta$ + one co-stimulatory domain (CD28 or 4-1BB)	Improved persistence and efficacy
3rd	CD3$\zeta$ + two co-stimulatory domains	Enhanced signalling
4th (“armoured”)	2nd gen + cytokine/ligand expression cassette	Modifies tumour microenvironment

FDA-approved CAR-T products (as of 2024) target CD19 (B cell malignancies) or BCMA (multiple myeloma):

Tisagenlecleucel (Kymriah) - CD19, 4-1BB/CD3$\zeta$
Axicabtagene ciloleucel (Yescarta) - CD19, CD28/CD3$\zeta$
Brexucabtagene autoleucel (Tecartus) - CD19, CD28/CD3$\zeta$
Lisocabtagene maraleucel (Breyanzi) - CD19, 4-1BB/CD3$\zeta$
Idecabtagene vicleucel (Abecma) - BCMA, 4-1BB/CD3$\zeta$
Ciltacabtagene autoleucel (Carvykti) - BCMA, 4-1BB/CD3$\zeta$

TCR-T cell therapy

TCR-engineered T cells are modified to express a specific TCR targeting a tumour-associated peptide-MHC complex. Unlike CAR-T cells, TCR-T cells can recognise intracellular antigens (presented via MHC class I), greatly expanding the range of targetable tumour antigens (e.g., NY-ESO-1, MAGE-A4, TP53 neoantigens).

Adoptive cell transfer (ACT)

Tumour-infiltrating lymphocytes (TILs) are harvested from a patient’s tumour, expanded ex vivo, and reinfused. TIL therapy has shown durable responses in melanoma and was FDA-approved in 2024 (lifileucel/Amtagvi).

sessionInfo()

R version 4.5.2 (2025-10-31)
Platform: x86_64-pc-linux-gnu
Running under: Ubuntu 24.04.4 LTS

Matrix products: default
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time zone: Etc/UTC
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other attached packages:
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Feature	TCR	Antibody (BCR)
Chains	\(\alpha\beta\) or \(\gamma\delta\)	Heavy + light
Antigen form	Peptide-MHC complex	Native antigen (any shape)
Secreted form	No	Yes (immunoglobulins)
Somatic hypermutation	No	Yes
Valency	Monovalent	Bivalent (or higher for IgM)
Isotype switching	No	Yes
Diversity mechanism	V(D)J recombination	V(D)J + SHM

Stage	CD44	CD25	Key events
DN1	+	-	Thymic entry, Notch signalling
DN2	+	+	TCR \(\beta\) gene rearrangement begins
DN3	-	+	\(\beta\)-selection checkpoint
DN4	-	-	Proliferation

Subset	Key transcription factor	Signature cytokines	Primary function
Th1	T-bet	IFN-\(\gamma\), TNF-\(\alpha\)	Intracellular pathogens, macrophage activation
Th2	GATA-3	IL-4, IL-5, IL-13	Helminth defence, allergic responses
Th17	ROR\(\gamma\)t	IL-17A, IL-17F, IL-22	Extracellular bacteria, fungi, mucosal defence
Tfh	Bcl-6	IL-21, IL-4	B cell help in germinal centres
Treg	FoxP3	IL-10, TGF-\(\beta\)	Immune suppression, self-tolerance
Th9	PU.1	IL-9	Anti-helminth, allergic inflammation
Th22	AHR	IL-22	Epithelial barrier function

Generation	Signalling domains	Features
1st	CD3\(\zeta\) only	Poor persistence and expansion
2nd	CD3\(\zeta\) + one co-stimulatory domain (CD28 or 4-1BB)	Improved persistence and efficacy
3rd	CD3\(\zeta\) + two co-stimulatory domains	Enhanced signalling
4th (“armoured”)	2nd gen + cytokine/ligand expression cassette	Modifies tumour microenvironment