CD4 1 T Cell Mediated Inflammation

Slide 1 · CD4+ T Cell–Mediated Inflammation

Type IV hypersensitivity · mechanisms · morphology · clinical examples

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how antigen-specific CD4+ T cells generate delayed inflammatory injury.

Compare Th1–macrophage and Th17–neutrophil pathways.

Recognize the time course and morphology of delayed-type hypersensitivity.

Relate contact dermatitis, granulomas, and selected diseases to mechanism.

Distinguish cytokine-driven inflammation from CD8+ cytotoxicity.

Antigen recognition

CD4+ Th1 / Th17 responses

Inflammatory leukocytes

Tissue injury

Slide 3 · Type IV hypersensitivity: The cellular arm

Cell-mediated hypersensitivity is driven mainly by cytokines from CD4+ T lymphocytes.

The resulting inflammation may be chronic and destructive.

CD8+ cytotoxicity is a distinct, sometimes coexisting, mechanism.

Tissue antigen

CD4+ effector cell

Cytokines

Inflammation / injury

Slide 4 · Prior sensitization is essential to classic DTH

An initial antigen encounter generates differentiated and memory T cells.

A subsequent tissue antigen challenge engages antigen-specific effector responses.

The visible reaction follows cellular recruitment and activation.

Initial encounter

Effector / memory pool

Repeat antigen

Tissue inflammation

Slide 5 · Why the reaction is delayed

0 h

Challenge

24–48 h

Detectable response

Later

Resolution / persistence

DTH is distinct from immediate hypersensitivity in its kinetics. • A cutaneous reaction becomes detectable after approximately 24–48 hours. • Timing reflects the cellular inflammatory response to antigen challenge.

Slide 6 · Two ways T cells injure tissues

CD4+ inflammation

CD8+ cell killing

Cytokines recruit and activate leukocytes

Recognized target cells are directly injured

Slide 7 · Three stages of CD4+ inflammatory injury

Antigen presentation + CD4+ activation

Effector Th1 / Th17 differentiation

Phagocyte recruitment / activation

Inflammation and tissue injury

The pathogenesis follows a causal sequence from recognition to tissue effect.

Slide 8 · Dendritic cells initiate antigen-specific activation

Naive CD4+ T cells recognize antigen-derived peptides displayed by dendritic cells.

The antigen-presenting cell supplies the context for clonal activation.

The primed population can later respond in tissue.

Dendritic cell + peptide

Naive CD4+ T cell

Activated clone

Slide 9 · Costimulation accompanies antigen recognition

Antigen recognition is the first activation signal.

B7 proteins (CD80/CD86) on antigen-presenting cells engage CD28 on naive T cells.

Antigen and costimulation cooperate in the initiating response.

MHC–peptide → TCR

B7 → CD28

CD4+ activation

Slide 10 · IL-2 expands the responsive T-cell clone

Antigen-stimulated CD4+ cell

IL-2 secretion / IL-2 receptor

Autocrine proliferation

Expanded antigen-specific pool

Activated CD4+ cells secrete IL-2 and express its high-affinity receptor.

IL-2 functions as an autocrine proliferation signal.

Clonal expansion increases the number of antigen-responsive cells.

Slide 11 · The APC cytokine milieu guides differentiation

Antigen-stimulated CD4+ T cell

IL-12 → Th1

IL-1 + IL-6 + IL-23 → Th17

The pattern of cytokines at initial activation helps determine helper-T-cell fate. Th1 and Th17 populations subsequently produce distinct inflammatory responses.

Slide 12 · IL-12 programs the Th1 pathway

Dendritic cells and macrophages can supply IL-12.

IL-12 induces differentiation toward the Th1 subset.

Th1 cells are linked to macrophage-dominant inflammatory injury.

APC / macrophage

IL-12

Th1 effector cell

Slide 13 · IFN-γ reinforces Th1 development

IL-12–driven Th1

IFN-γ

More Th1 differentiation

Amplified inflammatory response

Effector Th1 cells produce interferon-γ (IFN-γ).

IFN-γ promotes further Th1 development and amplifies the reaction.

It is also the principal macrophage-activating effector cytokine.

Slide 14 · IL-1, IL-6, and IL-23 support Th17 differentiation

Activated antigen-presenting cells produce inflammatory cytokines.

IL-1, IL-6, and IL-23 promote the Th17 pathway.

Th17 responses preferentially recruit neutrophils and monocytes.

Inflammatory APC

IL-1 · IL-6 · IL-23

Th17 effector cell

Slide 15 · Th1 and Th17 have different effector signatures

Feature

Th1 response

Th17 response

Inducing cytokines

IL-12

IL-1, IL-6, IL-23

Principal effector signals

IFN-γ

IL-17, IL-22, chemokines

Dominant recruited / activated cells

Activated macrophages

Neutrophils and monocytes

Common tissue pattern

Macrophage-rich inflammation

Neutrophil-rich component

Slide 16 · Memory cells enable rapid recall responses

Some differentiated T cells enter the circulation.

They become part of long-lived memory T-cell populations.

Persistent immune memory explains reactions to a later antigen encounter.

Differentiated effector cells

Circulation / memory pool

Repeat antigen

Slide 17 · Effector-phase responses require antigen re-exposure

Repeat tissue antigen

Memory / effector Th cell

Cytokine release

Inflammatory leukocytes

A primed Th1 or Th17 cell encounters its target antigen again.

Local cytokine production triggers inflammatory-cell recruitment.

The downstream phagocytes are major effectors of tissue injury.

Slide 18 · IFN-γ is the central Th1 effector signal

On repeat antigen encounter, Th1 cells produce IFN-γ.

IFN-γ produces the characteristic activated-macrophage response.

Sustained activation can turn a protective response into tissue injury.

Activated Th1

IFN-γ

Classically activated macrophage

Slide 19 · Classical macrophage activation changes cell function

IFN-γ signal

Macrophage activation

Microbe killing + antigen display

Cytokines + chemokines

IFN-γ induces a broad macrophage activation program.

Antimicrobial activity, antigen presentation, and inflammatory output all increase.

Slide 20 · Activated macrophages increase microbicidal activity

Macrophages acquire greater capacity to phagocytose microbes.

Their ability to kill ingested microorganisms is augmented.

This response is beneficial when the antigen is a persistent intracellular microbe.

Macrophage activation

↑ Phagocytosis

↑ Microbial killing

Slide 21 · Macrophage MHC II expression amplifies recognition

IFN-γ–activated macrophages express more MHC class II molecules.

Increased peptide display enhances interaction with helper T cells.

The macrophage becomes a stronger antigen-presenting participant.

Activated macrophage

↑ MHC class II

Enhanced T-cell interaction

Slide 22 · TNF and IL-1 convert activation into inflammation

Activated macrophages secrete TNF and IL-1.

These mediators promote local inflammatory changes.

Their continued production contributes to the damaging reaction.

IFN-γ–activated macrophage

TNF + IL-1

Inflammation

Slide 23 · Chemokines increase inflammatory-cell recruitment

Classically activated macrophages produce chemokines.

Chemokine-dependent recruitment expands the local infiltrate.

The recruited cells sustain the cytokine-driven lesion.

Macrophage chemokines

Leukocyte recruitment

Amplified infiltrate

Slide 24 · Macrophage IL-12 creates a reinforcing loop

Macrophage IL-12

Th1 activation

IFN-γ secretion

Macrophage activation

Activated macrophages can produce additional IL-12.

IL-12 supports the Th1 population that makes IFN-γ.

This positive-feedback architecture explains persistent activity.

Slide 25 · When host defense becomes tissue damage

Containment / defense

Persistence / pathology

Phagocytes eliminate the offending antigen

Antigen or stimulation persists

Macrophage activation supports microbial killing

Continued activation sustains inflammation

Response subsides when the trigger resolves

Repeated cytokine release injures tissue

Slide 26 · Th17 cells deploy IL-17 and IL-22

Activated Th17 cells secrete IL-17 and IL-22.

They also produce chemokines and additional cytokines.

Their combined output organizes a leukocyte-rich inflammatory reaction.

Th17 cell

IL-17 · IL-22

Chemokines

Slide 27 · Th17 responses recruit neutrophils and monocytes

Activated Th17

IL-17 / IL-22 / chemokines

Neutrophils + monocytes

Inflammatory tissue response

Th17-associated cytokines mobilize inflammatory leukocytes.

Neutrophils are a more prominent component than in classic Th1 responses.

Monocytes also enter the inflammatory tissue.

Slide 28 · Predict infiltrate composition from T-cell pathway

Feature

Th1-dominant

Th17-dominant

Key Th-cell cytokine

IFN-γ

IL-17 / IL-22

Characteristic phagocyte

Activated macrophage

Neutrophil, plus monocyte

Typical pathologic emphasis

Macrophage-rich inflammation

More prominent neutrophil component

Key diagnostic consideration:

Responses may coexist

Responses may coexist

Slide 29 · A unified map of CD4+ inflammatory injury

Antigen recognition

Th1 / Th17 cytokines

Inflammatory phagocytes

Tissue injury

Cytokines connect antigen-specific CD4+ cells to tissue injury.

The principal route differs by the Th1 or Th17 effector program.

Slide 30 · DTH: A recall reaction in previously immunized skin

Delayed-type hypersensitivity (DTH) is the classic model of CD4+ inflammation.

Antigen is introduced into skin of a sensitized individual.

The response develops over hours rather than immediately.

Previously sensitized host

Skin antigen challenge

Local delayed inflammation

Slide 31 · Tuberculin is an antigenic recall challenge

Purified protein derivative (PPD; Tuberculin) contains antigen from the tubercle bacillus.

An intradermal challenge elicits DTH in a previously sensitized individual.

The reaction illustrates a local, antigen-specific inflammatory memory response.

PPD introduced into skin

Primed T-cell recognition

Induration / erythema

Slide 32 · The tuberculin reaction has a characteristic course

8–12 h

Onset

24–72 h

Peak response

Thereafter

Gradual resolution

Redness and induration begin after about 8–12 hours. • The response peaks around 24–72 hours. • The local lesion then gradually subsides.

Slide 33 · DTH morphology: Perivascular mononuclear cuffing

CD4+ lymphocytes and macrophages collect around dermal venules.

Their perivascular aggregation produces a cuff-like infiltrate.

This is the classic microscopic pattern of the cellular reaction.

Venule

Perivascular mononuclear cuff

Schematic — not a histologic specimen

Slide 34 · Endothelial hypertrophy accompanies activation

Fully developed DTH lesions show hypertrophic venular endothelial cells.

The change reflects cytokine-mediated endothelial activation.

It accompanies the surrounding inflammatory-cell accumulation.

Venule

Perivascular mononuclear cuff

Schematic — not a histologic specimen

Slide 35 · Dermal edema and fibrin support the tissue reaction

The textbook DTH example includes dermal edema.

Fibrin deposition can accompany the perivascular mononuclear infiltrate.

These associated findings add context to the vascular-centered pattern.

Venule

Perivascular mononuclear cuff

Schematic — not a histologic specimen

Slide 36 · Anti-CD4 staining identifies the T-cell component

The illustrated source lesion contains a predominantly perivascular CD4-positive infiltrate.

Immunoperoxidase staining localizes the helper-T-cell component.

CD4 labeling supports cellular identity; It does not by itself establish the antigen.

Perivascular inflammatory cells

Anti-CD4 immunostain

CD4+ lymphocyte component

Slide 37 · Transient DTH versus sustained antigenic stimulation

Short-lived recall response

Persistent tissue stimulus

Cellular response peaks then subsides

Inflammation remains active

Perivascular T cells and macrophages

Macrophages increasingly predominate

Prototype: Tuberculin skin reaction

Possible progression to granulomatous inflammation

Slide 38 · Persistent antigens alter the cellular infiltrate

Exposure

Antigen persists

2–3 weeks

Macrophage dominance

Chronic

Granuloma

Indigestible or persisting antigens can maintain the response. • Macrophages become dominant over approximately 2–3 weeks. • The chronic response can organize into granulomas.

Slide 39 · Epithelioid cells are transformed macrophages

Sustained activation changes macrophage morphology.

They become larger, with abundant cytoplasm: Epithelioid cells.

Epithelioid transformation is a component of the granulomatous response.

Sustained stimulation

Activated macrophage

Epithelioid cell

Slide 40 · Granulomas organize macrophages and lymphocytes

Epithelioid macrophages form circumscribed cellular aggregates.

Lymphocytes commonly surround the activated macrophage core.

Such aggregates can form small visible granule-like nodules.

Epithelioid macrophage aggregate

Schematic — not a histologic specimen

Slide 41 · Strong Th1 activity favors immune granulomas

Persistent antigen

Th1 IFN-γ

Activated / epithelioid macrophages

Granuloma

Persistent antigen maintains helper-T-cell activation.

IFN-γ promotes sustained macrophage activation.

Aggregated activated macrophages characterize granulomatous inflammation.

Slide 42 · Granulomatous inflammation has diverse triggers

Trigger

Adaptive helper-T-cell context

Inflammatory character

Persistent mycobacterial antigen

Strong Th1 / IFN-γ response

Macrophage / epithelioid-rich

Indigestible foreign body

Adaptive T-cell response not required

Direct macrophage response

Schistosome eggs

Strong Th2 response

Eosinophil-rich granulomas

Slide 43 · Foreign bodies can produce nonimmune granulomas

An indigestible foreign material can activate macrophages.

Granuloma formation in this setting need not require adaptive immunity.

Thus, granuloma morphology alone does not establish a Th1 mechanism.

Indigestible foreign body

Macrophage recruitment

Granulomatous response

Slide 44 · Schistosomal eggs produce a different granuloma

Eggs deposited in tissues elicit granulomatous reactions.

The accompanying helper-T-cell response is commonly Th2-polarized.

Eosinophils are prominent in these granulomas.

Schistosome eggs

Th2 response

Eosinophil-rich granuloma

Slide 45 · Histology should be interpreted with mechanism

Observation

Potential explanation

Limit

Perivascular CD4+ mononuclear infiltrate

Delayed-type cellular inflammation

Antigen not identified by CD4 alone

Macrophage-rich epithelioid aggregate

Chronic / persistent activation

Foreign body or Th2 triggers possible

Prominent eosinophils in granuloma

Can accompany helminth-associated Th2 response

Not typical Th1-only pattern

Slide 46 · Contact sensitivity is an environmental DTH example

Poison ivy and poison oak contain urushiol, a trigger of contact sensitivity.

The clinical lesion is an itchy, vesicular dermatitis.

This is an example of delayed inflammatory skin injury.

Urushiol exposure

Antigenic modification

T-cell inflammation

Slide 47 · Small environmental chemicals can alter self proteins

Chemical contact

Modified self protein

T-cell recognition

Dermatitis

Environmental compounds may bind to self proteins and change their structure.

Peptides from modified proteins are then recognized by T cells.

The resulting response can damage the epidermis and dermis.

Slide 48 · Some chemicals alter HLA recognition directly

Certain chemicals can modify HLA molecules.

Altered HLA may appear foreign to T lymphocytes.

This is an alternative proposed route for chemical-elicited T-cell responses.

Chemical–HLA interaction

Altered T-cell recognition

Skin inflammation

Slide 49 · Drug reactions may use related T-cell mechanisms

Similar immunologic reactions account for many drug hypersensitivity presentations.

Skin rash is a common clinical manifestation.

A chemical–protein or HLA interaction is a possible initiating mechanism.

Drug-associated antigenic change

T-cell response

Cutaneous rash

Slide 50 · Contact dermatitis: Cause and morphology

Mechanism

Tissue manifestation

Urushiol or other chemical exposure

Pruritic skin eruption

Altered self proteins / possible altered HLA

T-cell mediated inflammatory response

Tissue inflammation and injury

Epidermal necrosis, dermal inflammation and blisters

Slide 51 · Three classic manifestations of CD4+ inflammation

Setting

Dominant lesson

Typical lesion

Tuberculin skin response

Antigen-specific delayed recall

Erythema / induration; Mononuclear cuffing

Persistent antigen

Chronic macrophage activation

Epithelioid granuloma

Contact sensitivity

Chemically modified antigenic target

Pruritic vesicular dermatitis

Slide 52 · Selected disorders associated with Th1 / Th17 pathways

Disease

Pathway noted

Tissue consequence

Rheumatoid arthritis

Th17; Possible Th1, antibody / complex roles

Chronic destructive arthritis

Multiple sclerosis

Th1 and Th17; Activated macrophages

Inflammatory CNS demyelination

Inflammatory bowel disease

Th1 and Th17

Chronic intestinal inflammation

Psoriasis

Mainly Th17 cytokines

Inflammatory skin plaques

Slide 53 · Rheumatoid arthritis: Multiple mechanisms may overlap

Th17 cytokines are implicated; A Th1 contribution is discussed as possible.

Antibodies and immune complexes may also contribute.

The resulting chronic synovial inflammation damages articular cartilage.

Joint-directed immune response

Th17 ± Th1 cytokines

Antibodies / immune complexes?

Chronic destructive arthritis

Slide 54 · Multiple sclerosis: Inflammation and myelin injury

The proposed pathogenic T-cell targets include myelin proteins.

Th1/Th17 cytokines and activated macrophages contribute to myelin destruction.

Consequences include inflammatory CNS demyelination and neurologic deficits.

Myelin-related antigens

Th1 / Th17 + macrophages

CNS demyelination

Slide 55 · Inflammatory bowel disease and commensal responses

Uncontrolled responses to enteric bacteria are implicated.

Th1 and Th17 cytokines participate in intestinal inflammation.

Sustained mucosal injury causes chronic intestinal pathology.

Enteric bacterial antigens

Th1 / Th17 response

Chronic intestinal inflammation

Slide 56 · Psoriasis: Prominent Th17 cytokine involvement

The source describes the pathogenic T-cell antigen as unknown.

Th17-derived cytokines are the principal emphasized inflammatory mechanism.

The clinical lesion consists of inflammatory plaques of skin.

Unknown antigenic trigger

Th17 cytokines

Cutaneous plaques

Slide 57 · Type 1 diabetes: Inflammation plus CTL cell killing

Pancreatic islet antigens are implicated in the T-cell response.

Insulitis denotes chronic inflammatory infiltration of the islets.

CD8+ CTL destruction of β cells is a major injury mechanism.

Pancreatic islet antigens

Chronic islet inflammation

CD8+ cytotoxic β-cell injury

Loss of β cells

Slide 58 · T-cell disease mechanisms are not all the same

Disease

Inflammatory component

Direct cytotoxic component

Rheumatoid arthritis

Th17 ± Th1 cytokines

Not primary mechanism in table

Multiple sclerosis

Th1 / Th17, macrophage injury

Not primary mechanism in table

Type 1 diabetes

Islet inflammation

CD8+ CTLs destroy β cells

Contact sensitivity

Th1 ± Th17 inflammatory injury

Not specified as primary in Table 6.5

Slide 59 · CD4+ inflammation versus CD8+ cytotoxicity

Criterion

CD4+ T-cell inflammation

CD8+ CTL injury

Main T-cell action

Secretion of inflammatory cytokines

Target-cell killing

Typical proximal effector

Macrophages / recruited leukocytes

Perforin- and granzyme-mediated apoptosis

Antigen context

Tissue antigens presented by APCs

Target antigen displayed by infected or altered cells

Dominant tissue effect

Inflammation and secondary injury

Loss of antigen-bearing target cells

Slide 60 · Type IV differs from antibody-mediated injury

Mechanism

Principal mediator

Common injury process

T-cell mediated (type IV)

CD4+ cytokines and/or CD8+ cells

Cellular inflammation and/or direct killing

Antibody-associated (type II)

Antibodies to cellular / tissue targets

Opsonization, inflammation or receptor dysfunction

Immune complex (type III)

Deposited antigen–antibody complexes

Complement-driven inflammatory damage

Slide 61 · Interpreting a suspected cellular hypersensitivity lesion

Identify the dominant infiltrating cells and their tissue distribution.

Ask whether the trigger is a repeat antigen exposure or a persistent stimulus.

Distinguish a cytokine-associated phagocyte response from direct CTL cytolysis.

Correlate lesion morphology with clinical context; A single stain is not definitive.

Which cells dominate the infiltrate?

Was there sensitization or persistence?

Cytokine activation or direct cytolysis?

Integrate morphology with exposure

Slide 62 · Caution: Disease mechanisms are partly inferred

Many pathogenic T-cell specificities remain uncertain.

Some human disease mechanisms are inferred from experimental animal models.

A Th1 or Th17 association is not proof of an exclusive pathway.

Avoid turning candidate antigens into established diagnostic biomarkers.

Antigen specificity ≠ always known

Mechanistic overlap is common

Inference is not direct proof

Slide 63 · Case exercise: An indurated skin reaction

A sensitized person develops an indurated reaction after an intradermal antigen challenge.

Which immune-cell program and tissue morphology best explain the delayed response?

Identify the expected timing of peak inflammatory activity.

Antigen recall

Th1 IFN-γ

Perivascular T cells / macrophages

Slide 64 · Case discussion: Delayed skin reaction

The mechanism is a delayed, antigen-specific CD4+ T-cell inflammatory response.

IFN-γ activates macrophages; Perivascular mononuclear cuffing is expected.

For tuberculin, erythema and induration peak about 24–72 hours after challenge.

Memory / effector CD4+ cells

IFN-γ macrophage activation

Induration / cuffing

Slide 65 · Case exercise: Vesicles after plant contact

An individual develops a pruritic vesicular rash after poison ivy exposure.

Explain how a small environmental chemical can trigger T-cell immunity.

Predict the broad epidermal and dermal injury pattern.

Urushiol exposure

Modified host targets

Delayed dermatitis

Slide 66 · Case discussion: Contact sensitivity

Urushiol can alter self proteins and render derived peptides recognizable to T cells.

Chemical modification of HLA is another possible mechanism.

T-cell inflammation produces dermal infiltrates, epidermal injury and vesicles.

Chemical modifies self/HLA

T-cell recognition

Epidermal / dermal injury

Slide 67 · Case exercise: A macrophage-rich nodule

Persistent tissue antigen is followed by a circumscribed epithelioid-cell aggregate.

Which effector cytokine and helper-T-cell subset favor this pattern?

Name a non–Th1-dependent alternative pathway to granuloma formation.

Persistent stimulation

Epithelioid macrophages

Granuloma

Slide 68 · Case discussion: A granulomatous response

Strong Th1-derived IFN-γ promotes sustained macrophage activation.

Epithelioid macrophages aggregate and are often rimmed by lymphocytes.

Indigestible foreign bodies or Th2 responses to schistosome eggs are alternatives.

Th1 IFN-γ (one cause)

Macrophage transformation

Granuloma

Slide 69 · Core mechanistic synthesis

APC + CD4+ priming

Th1 IFN-γ / Th17 cytokines

Macrophages / granulocytes

Inflammation ± injury

The type of cytokine response helps predict recruited cell populations.

Persistent stimulation, not cytokine identity alone, determines chronicity.

Slide 70 · Five essential conclusions

CD4+ T cells induce tissue injury chiefly through cytokine-driven inflammation.

Th1–IFN-γ responses activate macrophages; Th17 promotes neutrophil-rich recruitment.

Classic DTH is delayed and produces perivascular mononuclear inflammation.

Persistent activation may generate epithelioid-cell granulomas.

Clinical examples differ in triggering antigen, inflammatory cells and injury pathway.

Antigen recognition

CD4+ Th1 / Th17 responses

Inflammatory leukocytes

Tissue injury

Slide 71 · Primary reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026).

Chapter 6, Diseases of the Immune System; section “T Cell–Mediated (Type IV) Hypersensitivity,” pp. 189–191.

Additional contextual sections: T-cell activation and cell-mediated immunity (pp. 177–178).

Textbook Table 6.5 and Figures 6.18–6.19 informed original editable teaching diagrams; images were not reproduced.