T-Cell-Mediated (Type IV)

Hypersensitivity
 T-Cell-Mediated (Type IV)
Hypersensitivity
• The cell-mediated type of hypersensitivity is
caused by inflammation resulting from cytokines
produced by CD4+ T cells and cell killing by CD8+
T cells.
• Two types of T-cell reactions are capable of
causing tissue injury and disease:
– Delayed-type hypersensitivity; initiated by
CD4+ T cells
– Direct cell cytotoxicity; mediated by CD8+ T
cells
 Delayed-Type Hypersensitivity
Activation of CD4+ T Cells
Naïve CD4+ T cells recognize peptides displayed by
APCs and secrete IL-2
IL-2 functions as autocrine growth factor to stimulate
proliferation of T cells
Cytokines produced by APCs causes differentiation of
CD4+ T cells to TH1 or TH17 cells
If APCs produce IL-12, CD4+ T cells are differentiated
into the TH1 subset
If the APCs produce cytokines such as IL-1, IL-6, and IL-
23, CD4+ T cells are differentiated to the TH17 subset
Responses of Differentiated Effector T Cells

• TH1 cells secrete cytokines, mainly IFN-γ,

which are responsible for activation of
macrophages.
• TH17 cells secrete IL-17, IL-22, which recruit
neutrophils to the reaction.
Delayed-Type Hypersensitivity
 Example of DTH:
Tuberculin reaction (Mantoux test)
• Produced by the intracutaneous injection of
purified protein derivative (PPD, also called
tuberculin), a protein-containing antigen of
the tubercle bacillus
• In a previously sensitized individual, reddening
and induration of the site appear in 8 to 12
hours, reach a peak in 24 to 72 hours, and
thereafter slowly subside.
Only reactions of 10 or
more mm are likely to
indicate previous
tuberculous infection.
 Granulomatous inflammation

• Prolonged DTH reactions against persistent or

nondegradable antigens, such as tubercle
bacilli or other stimuli may result in a special
morphologic pattern of reaction called
Granulomatous Inflammation.
Granulomatous inflammation
• With sustained activation, macrophages often
undergo a morphologic transformation into
epithelioid cells, large epithelium-like cells
with abundant cytoplasm.
• The epithelioid cells occasionally fuse to form
multinucleated giant cells.
• “Aggregate of epithelioid cells, surrounded by
of lymphocytes and plasma cells, is called a
granuloma”
Granulomatous inflammation
 Contact dermatitis
• Contact dermatitis is an example of tissue
injury resulting from DTH.
• Contact dermatitis is a condition in which the
skin becomes red, sore, or inflamed (vesicular
dermatitis) after direct contact with a
substance e.g poison ivy poison oak.
CD8+ T Cell–Mediated Cytotoxicity
In this Class I MHC molecules bind to antigens and present
the peptides to CD8+ T cells, stimulating the differentiation
of these T cells into effector cells called CTLs.
The principal mechanism of killing by CTLs is dependent on
the perforin-granzyme system
Perforin binds to the plasma membrane of the
target cells and promotes the entry of granzymes

Granzymes, are proteases that specifically cleave

and thereby activate cellular caspases.

Caspases induce apoptotic death of the target

cells.
Examples of T Cell–Mediated (Type IV) Hypersensitivity

Disease Specificity of Pathogenic T Cells

Type 1 diabetes mellitus Antigens of pancreatic islet β cells

Multiple sclerosis Protein antigens in CNS myelin

Rheumatoid arthritis Unknown antigen in joint synovium

Crohn disease Unknown antigen; role for

commensal bacteria
Peripheral neuropathy; Protein antigens of peripheral nerve
Guillain-Barré syndrome? myelin
Contact sensitivity Various environmental antigens
(dermatitis) (e.g., poison ivy)