Cytotoxic and helper T lymphocytes

A T cell that meets its peptide on a dendritic cell divides into thousands of copies, and they become effector cells. CD8 T cells kill infected cells. CD4 T cells, the helpers, direct the rest of the response with cytokines and with contact.

12 min read
6 questions
Checked 29 Oct 2026

What armed T cells do

6 scenes, 0:55

A film in six scenes on a white page, drawn flat and soft like the helper-subset and killing figures. First, a periwinkle dendritic cell with long tapering processes. Small round T cells pass it by; one comes to rest against it, between two processes. Light green IL-2 receptors appear round the T cell, pink dots of IL-2 leave it and come back to sit on them, and the T cell grows larger. It moves off and divides, and its daughters divide, four times, into a cluster of sixteen cells beside the dendritic cell. Next, a large periwinkle macrophage with a bean-shaped nucleus and two khaki rod-shaped bacteria, each in a phagosome ringed by an amber membrane, and pink lysosomes scattered round. A T cell comes to rest against its right side; both cells flatten at the contact, where green receptors on the T cell meet green class II molecules carrying khaki peptides, and CD40 ligand meets CD40. Pink dots of interferon-γ cross the narrow cleft to receptors on the macrophage. The lysosomes travel to the phagosomes and merge into them, the phagosomes turn pink inside, and the bacteria break into short chains of khaki beads. Then a round B cell with deep green Y-shaped receptors standing out of its surface, and a T cell coming to rest against it; at the contact the same pairs of molecules meet, and pink dots of IL-21 cross. The T cell moves away and the B cell turns into a larger oval plasma cell, its nucleus to one side, a pale blue Golgi beside it and lilac sheets of ER curving round it, and green Y-shaped antibodies drift out of it. Then a row of peach epithelial cells with lavender nuclei, green class I molecules on their tops holding small peptides in the cells' own colour, and between them deeper green ICAM-1. Two of the cells hold small viral genomes and teal viral peptides on their class I. A periwinkle T cell with pink granules crawls along their tops, its receptors underneath and its LFA-1 bent. Over the first infected cell it stops and spreads flat, and its LFA-1 stands up and grips ICAM-1. Then a close-up of the two cells side by side, the T cell on the left and the infected cell on the right: thin green microtubules ray out from the T cell's centrosome, which moves round under the nucleus to the contact, the blue Golgi with it, and the pink granules gather there. One granule opens onto the cleft, two green perforin walls appear in the infected cell's membrane, and small green granzymes cross through the gap into its cytoplasm, among its salmon mitochondria; then green caspase dots and smaller cytochrome c dots appear. Last, back to the row of cells: the T cell lets go and crawls on to the second infected cell, where it stops and grips again, while the cell it hit blebs, its nucleus breaks into blue pieces, and it shrinks and falls apart into small round bodies, its neighbours untouched.

0:00 / 0:55

Scene 1 of 6

One T cell becomes a clone

Many naive T cells pass a dendritic cell; the one whose receptor fits a peptide it shows stops. With co-stimulation it makes IL-2 and the α chain of the IL-2 receptor, which makes the receptor bind IL-2 tightly, grows into a blast and divides two to three times a day for several days, into a clone of thousands of armed effector cells.

Scenes

About this film

Once armed, helper T cells act through cytokines and CD40 ligand on the cells that show them their peptide, and cytotoxic T cells kill infected cells one at a time, by apoptosis.

Simplified: not to scale: the molecules drawn far larger than the cells, and one of each standing for many; the dendritic cell's MHC and co-stimulatory molecules too small to draw at the first scene's scale; the T cell is shown resting against it; the IL-2 receptor drawn as one stalk; it has three chains, of which the T cell adds the α chain, CD25; four rounds of division in a few seconds; a real clone divides for several days, into thousands of cells, and then differentiates; the macrophage's other changes when activated, such as nitric oxide, oxygen radicals and more class II, not drawn; the macrophage's activation and the infected cell's death, which take hours, shown in seconds; the B cell drawn turning straight into a plasma cell; it first divides, in a germinal centre, over days, and some of its daughters become memory cells instead; the tissue drawn as a row of cells with the T cell crawling over their tops; in a tissue it moves among the cells; self peptides on the healthy cells' class I drawn in the cell's own colour, the viral peptide in the virus's; CD2 and its partner, which also hold the cells together, left out; the close-up of the attack drawn from the side, as in the figure, the T cell on the left; granzymes drawn entering through the perforin pore; some may be taken up into the cell in a vesicle first; the phagocytes that eat the apoptotic bodies not drawn; the viral genomes drawn whole in the apoptotic bodies; the nucleases of apoptosis can cut viral DNA.

4 sources

Contents4 sections

At a glance

A naive T cell that meets its peptide with co-stimulation makes IL-2 and its receptor, divides two to three times a day for several days, and its thousands of progeny become armed effector T cells, which need no co-stimulation to act and leave for the tissues.
CD8 T cells become cytotoxic T lymphocytes (CTLs). They find cells showing their peptide on MHC class I, mostly virus-infected cells, and make them die by apoptosis.
CTLs kill mainly with perforin and granzymes, stored in lytic granules and released only at the point of contact; perforin makes pores, granzymes enter and trigger caspases. Fas ligand and cytokines are their other weapons.
CD4 T cells become helpers, of kinds set by the cytokines present when they are primed: Th1 (IL-12) activate macrophages, Th2 (IL-4) drive IgE and eosinophils, Th17 (TGF-β with IL-6) call in neutrophils, and follicular helpers (Tfh) help B cells make antibody.
Helpers act through cytokines and through CD40 ligand, which switches on macrophages, B cells and dendritic cells. Through dendritic cells they help start CD8 responses too.
Losing a subset leaves a typical gap: CD4 loss in HIV gives opportunistic infections, a broken IL-12 and interferon-γ pathway gives mycobacterial disease, absent Th17 cells give staphylococcal and Candida infections.

From naive to armed

A naive T cell can circulate for years without dividing, a small cell with little cytoplasm, passing through lymph node after lymph node. When it meets its peptide on a dendritic cell that also gives it co-stimulation, it changes. It makes interleukin-2 (IL-2) and the α chain of the IL-2 receptor, CD25, which makes the receptor bind IL-2 tightly, and so drives its own division. It divides two to three times a day for several days, and one cell becomes a clone of thousands, all with the same receptor.

After four to five days the clone differentiates into armed effector T cells, which make the molecules of their particular job. Three things set them apart from the naive cell they came from.

No second signal. An armed effector cell acts on its peptide alone, without co-stimulation. This is what lets a cytotoxic T cell kill an infected cell that cannot co-stimulate, and a helper switch on a B cell or macrophage that has little CD80 or CD86.
New homing. It loses L-selectin, which took it into lymph nodes, and gains the integrin VLA-4, which binds the inflamed endothelium of infected tissue. It leaves the lymph node for where the infection is.
A tighter grip. It has more LFA-1 and CD2, so it can hold on to target cells with less ICAM than a dendritic cell has.

CD4 T cells make up about two thirds of the T cells in blood, CD8 T cells about one third. Naive CD8 T cells are already set to become killers. Naive CD4 T cells are not set: what kind of helper each becomes is decided while the clone divides.

Helper T cells

CD4 T cells help in many ways. They help B cells make antibody, help CD8 T cells, direct macrophages, call in other cells, and restrain responses once they have done their work. Each kind of helper does part of this, and the kind is set by the cytokines around the T cell while it divides, made mostly by the innate cells that met the microbe first. Each kind has a master transcription factor that sets up its programme and holds the others off.

The kinds of helper T cell

Point at a name to light its pathway.

What a helper becomes is set by the cytokines around it while it divides, made mostly by the innate cells that met the microbe first. Each kind then calls in the defence that suits one sort of microbe.

Simplified: a map of who acts on whom, not a picture of the cells; the four kinds drawn as separate fates; in the body they overlap, and some cells change from one kind to another; only the main cytokines that drive each kind; IL-21 can stand in for IL-6, and Th2 cells also need IL-2; only each kind's signature products; Th1 cells also make TNF and IL-2, and Tfh cells make IL-4 later; regulatory T cells, a fifth kind with FOXP3, and rarer kinds such as Th9 and Th22 left out; the help CD4 T cells give CD8 T cells, through dendritic cells, left out; one cell drawn for each column's targets; the B cells a follicular helper helps drawn as the plasma cell many become.

5 sources

Kumar and Clark's Clinical Medicine, 10th edition. Elsevier, 2021. Chapter 3, Immunity: Box 3.12 and the T helper subsets (pp. 51–52); allergy (p. 62).
Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 5th edition. Garland Science, 2001. Chapter 8, sections 8-13 and 8-26.
Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010;28:445–489.
Crotty S. T follicular helper cell biology: a decade of discovery and diseases. Immunity. 2019;50(5):1132–1148.
Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. 2023;23(1):38–54.

	Th1	Th2	Th17	Tfh
Made when primed with	IL-12, interferon-γ	IL-4	TGF-β with IL-6 (IL-21, IL-23)	dendritic cells first, then contact with B cells
Master factor	T-bet	GATA3	RORγt	Bcl-6
Makes	interferon-γ, TNF, IL-2	IL-4, IL-5, IL-13	IL-17, IL-22	IL-21, IL-4, CD40 ligand
Acts on	macrophages, CD8 T cells	eosinophils, mast cells, B cells (IgE)	neutrophils, epithelia	B cells in follicles
Defends against	microbes inside cells, such as mycobacteria	helminths	extracellular bacteria and fungi	most pathogens, through antibody
Overactive in	granulomas, some autoimmunity	allergy, asthma	psoriasis, spondyloarthritis	autoantibody diseases such as lupus

A fifth kind, the regulatory T cell, with the factor FOXP3 and much CD25, holds the others back with IL-10, TGF-β and contact. It is a topic of its own.

Th1 cells and the macrophage

Many microbes are eaten by macrophages and some, such as Mycobacterium tuberculosis and Leishmania, live on inside them, in the very vesicles meant to kill them. A resting macrophage cannot finish them off. The main work of a Th1 cell is to activate it.

The macrophage needs two signals. One is interferon-γ, the Th1 cell's signature cytokine. The other, which makes the macrophage able to respond, is CD40 ligand on the T cell binding CD40 on the macrophage. The Th1 cell makes both only when it sees its peptide on the macrophage's class II, and delivers them at the point of contact, so the infected macrophage is activated and its neighbours much less.

An activated macrophage fuses its lysosomes with its phagosomes far more readily, makes oxygen radicals and nitric oxide, and puts out more class II, CD80, CD86 and CD40, so it presents better to fresh T cells. It secretes TNF and IL-12, which drives more Th1 cells. Activation also damages tissue, which is why it is kept local and short-lived.

When a microbe resists even activated macrophages, the response walls it off: a granuloma, a core of macrophages, some fused into giant cells, ringed by lymphocytes, as in tuberculosis.

Th2 cells

Th2 cells make IL-4, IL-5 and IL-13. IL-4 switches B cells to make IgE, IL-5 drives the production and survival of eosinophils, and together they arm mast cells and eosinophils against helminths, parasitic worms too big to eat. The same response, aimed at harmless pollen or dust mite, is allergy: Th2 cells recognising the allergen sustain the late phase of an allergic reaction and the chronic inflammation of allergic asthma. IL-4 and IL-13 also hold back macrophage activation, and each subset's master factor holds the other's programme off, so Th1 and Th2 responses tend to exclude each other.

Th17 cells

Th17 cells make IL-17 and IL-22, and so do some other T cells and innate cells. These cytokines call in neutrophils, make barrier epithelia such as the skin and gut lining produce antimicrobial peptides, and strengthen the barrier, a defence against extracellular bacteria and fungi, Candida above all. IL-23 from dendritic cells and macrophages keeps the Th17 population growing.

The same cytokines drive chronic inflammatory disease. Drugs that block IL-17 work well in psoriasis. In the gut the picture is mixed: IL-17 is raised in Crohn's disease, but it also protects the gut lining, and in trials blocking it brought more bowel inflammation and more Candida infections, while blocking IL-23 helps.

Follicular helper cells and B cells

Follicular helper T cells (Tfh) are the helpers specialised for B cells. Their factor, Bcl-6, gives them CXCR5, a chemokine receptor that draws them to the edge of the B-cell follicles. There they meet B cells that have taken in the same antigen and show its peptide on class II. CD40 ligand binding CD40 and the cytokine IL-21 make the B cell divide, form a germinal centre and become a plasma cell or a memory cell. Without CD40 ligand, B cells cannot switch from IgM to the other classes. Which class they switch to depends on the cytokines: IL-4 for IgE, for example.

Help for CD8 T cells

Naive CD8 T cells need more co-stimulation than naive CD4 T cells. A dendritic cell can give it directly. Often, though, a CD4 T cell recognising the same antigen on the same dendritic cell is needed first: its CD40 ligand binds CD40 on the dendritic cell and licenses it, raising its CD80 and CD86 until it can start the CD8 T cell. This is a check that a killer, which does so much damage, is started against an antigen that helpers recognise too.

Cytotoxic T cells

A cytotoxic T lymphocyte (CTL) kills cells that show its peptide on MHC class I: above all virus-infected cells, and also cells infected with bacteria that live in the cytosol, tumour cells, and the cells of a foreign graft. It kills by making them die by apoptosis, programmed cell death, rather than bursting them, and does it with great precision.

How a cytotoxic T cell kills

Step 1 of 5Find and hold. The T cell's receptor finds its viral peptide on class I. LFA-1 then grips ICAM-1 hard, sealing the contact in a ring round the receptors.

Point at a name or a part to light it.

A cytotoxic T cell kills by making its target take itself apart. It aims its granules at one cell at a time, so the cells around it are spared.

Simplified: not to scale; the cleft and the molecules in it drawn far larger than they are; the ring of LFA-1 and ICAM-1 drawn in section, as a pair above and a pair below; two receptors drawn for the many that gather in the contact; CD8 and CD2 left out of the contact; granzymes drawn entering through the perforin pore; some may be taken up into an endosome first; Bid, the other caspases and the DNase that cuts the DNA left out; Fas ligand binding Fas, the T cell's second way to kill, left out; the dead cell's break-up drawn at once; it takes hours; the viral genomes drawn whole in the apoptotic bodies; the nucleases of apoptosis can cut viral DNA.

4 sources

Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 5th edition. Garland Science, 2001. Chapter 8, sections 8-12, 8-15, 8-16 and 8-21 to 8-24.
Chowdhury D, Lieberman J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu Rev Immunol. 2008;26:389–420.
Lopez JA, Susanto O, Jenkins MR, et al. Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood. 2013;121(14):2659–2668.
Silverthorn DU. Human Physiology, An Integrated Approach, 8th edition. Pearson, 2019. Chapter 24, The immune system: cytotoxic T cells (p. 772).

1
Find and hold
The CTL binds cells loosely with LFA-1 and CD2 as it crawls over them. When its receptor finds its peptide on class I, LFA-1 grips ICAM-1 hard, sealing a ring of tight contact round the receptors, the immunological synapse.
2
Aim
The CTL turns its secretory machinery towards the contact: its microtubule-organising centre and Golgi move up to the synapse, and the lytic granules, modified lysosomes, gather round them.
3
Release
The granules fuse with the membrane in the synapse and empty into the narrow cleft. Perforin polymerises into pores in the target's membrane, and granzymes, proteases, get in through them, though some may first be taken up into the cell in a vesicle.
4
Death from within
Granzyme B cuts after aspartate, like the caspases. It activates caspase-3, the executioner, and cuts Bid, which makes the mitochondria release cytochrome c. Caspase-activated DNase cuts the DNA, and the cell shrinks and breaks into fragments that phagocytes eat.
5
On to the next
The CTL lets go and finds another target. It makes more perforin and granzymes as it goes, so one cell can kill many in turn.

A target is programmed to die within about five minutes of contact, though it takes hours to fall apart. The granule contents are kept from working inside the granule and released only into the synapse, one target at a time, so neighbouring uninfected cells are spared. That matters most where cells are not replaced, such as neurons.

Apoptosis is the right way for an infected cell to die. Its nucleases can cut viral DNA as well as the cell's, which stops new virions being assembled, and the shrunken cell is eaten by phagocytes quietly, without inflammation. A burst cell would release live virus.

CTLs have two other weapons.

Fas ligand on the CTL binds Fas, a death receptor on the target, which activates caspase-8 and then caspase-3. Th1 cells use it too. Activated lymphocytes carry Fas themselves, and this route helps end a response once the microbe is gone; its inherited defects cause autoimmune lymphoproliferation.
Cytokines. CTLs make interferon-γ and TNF. Interferon-γ hinders viral replication, raises class I on nearby cells so infected ones are seen better, and activates macrophages.

of an activated T cell, for several days: 2–3divisions a day
from activation to armed effector cells: 4–5days
for a CTL to program its target to die: 5minutes

CD8 and CD4 T cells side by side

	Cytotoxic T cells	Helper T cells
Co-receptor	CD8	CD4
Read peptides on	MHC class I, on almost any cell	MHC class II, on dendritic cells, macrophages, B cells
Effector molecules	perforin, granzymes, Fas ligand; interferon-γ, TNF	cytokines; CD40 ligand
Made when	perforin and granzymes stored in granules in advance, released within minutes; cytokines made after contact	made anew after contact, over hours
Main targets	infected and tumour cells, which they kill	macrophages, B cells, dendritic cells, other T cells, which they activate

Clinical link

HIV. HIV infects CD4 T cells through CD4 and destroys them. The CD4 count is used to follow the infection, and opportunistic infections, such as Pneumocystis pneumonia, become likely when it falls below 200 cells per mm³.

When the Th1 pathway breaks. Inherited defects of the IL-12 and interferon-γ pathway, in the genes for the IL-12 receptor, IL-12 itself, the interferon-γ receptor or STAT1, cause Mendelian susceptibility to mycobacterial disease: severe infection with BCG, non-tuberculous mycobacteria and tuberculosis, and with Salmonella, while most other infections are handled normally.

When Th17 cells are missing. In autosomal dominant hyper-IgE (Job's) syndrome, a dominant-negative STAT3 mutation stops Th17 cells forming. Patients have eczema, staphylococcal boils, pneumonias that leave cysts, chronic Candida infection, bone and dental abnormalities, and very high IgE.

When help for B cells fails. In X-linked hyper-IgM syndrome, CD40 ligand is defective: B cells cannot switch class, so IgG and IgA are low or absent while IgM is normal or high. CD40 ligand also helps T cells activate macrophages, and opportunistic infections such as Pneumocystis and Cryptosporidium are typical.

When killing fails. Inherited defects of perforin, or of the machinery that releases the granules, cause familial haemophagocytic lymphohistiocytosis, a life-threatening hyper-inflammatory syndrome of young children, often set off by a virus. Chédiak–Higashi syndrome, a defect of lysosome trafficking, can cause the same picture. A stem cell transplant is the only cure.

One microbe, two diseases. In leprosy, a strong Th1 response gives tuberculoid disease, few bacilli and local nerve damage; a weak one gives lepromatous disease, with bacilli spread widely. The Mantoux skin test, a delayed-type hypersensitivity reaction read two to three days after the injection, and the interferon-γ release assays for tuberculosis both detect T cells that remember the bacillus.

Drugs aimed at the helpers' cytokines. Ustekinumab blocks IL-12 and IL-23 (psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis); secukinumab blocks IL-17A (among others psoriasis, psoriatic arthritis, axial spondyloarthritis); dupilumab blocks the receptors for IL-4 and IL-13 (among others atopic dermatitis and asthma with type 2 inflammation); mepolizumab blocks IL-5 (among others severe eosinophilic asthma).

Check yourselfAnswer, then say how sure you were: a lucky guess still counts as a weak point.

1An armed effector CD8 T cell meets a virus-infected epithelial cell that makes no CD80 or CD86. What happens?

2A naive CD4 T cell is primed by a dendritic cell that makes IL-12. Which kind of helper is it most likely to become, and what does it then do?

3Which two signals does a Th1 cell give a macrophage to activate it?

4How do perforin and granzymes kill a target cell together?

5Why is it better for a cytotoxic T cell to make an infected cell die by apoptosis than to burst it?

6A child with recurrent staphylococcal boils, pneumonias that leave cysts and chronic Candida infection has very high IgE and a dominant-negative STAT3 mutation. Loss of which helper cells explains these infections?

See on the map

Cytotoxic and helper T lymphocytes