T cells-PART III

FUNCTIONS OF EFFECTOR CD4+ T CELLS

Cooperation of CD4+ and CD8+ T cells in defense against intracellular microbes. Intracellular bacteria such as L. monocytogenes are phagocytosed by macrophages and may

survive in phagosomes and escape into the cytoplasm. CD4+ T cells respond to class II MHC-associated peptide antigens derived from the intravesicular bacteria. These T cells produce IFN-gamma;, which activates macrophages to destroy the

microbes in phagosomes. CD8+ T cells respond to class I-associated peptides derived from cytosolic antigens and kill the infected cells.

Intracellular bacteria-Listeria

monocytogenes,

Mycobacterium leprae,Mycobacterium tuberculosis

These microbes use evasionmechanisms to prevent theirdestruction by macrophages

Adaptive immune responses to extracellular microbes, such as bacteria, and their toxins consist of antibody production and the activation of CD4+ helper T

cells. Antibodies neutralize and eliminate microbes and toxins by several mechanisms. Helper T cells produce cytokines that stimulate B cell responses,

macrophage activation, and inflammation. (Abbas).

Adaptive immune responses to extracellular microbes.

(Abbas

AK., Lichtamn

AH, Pillai

,S.)

Functions of human Ig

classes and subclasses

IgG1 and IgG3 -IFN-γ-Th1 (signature cytokine)IgE, IgA-IL-4 and IL-5-Th2 (signature cytokine)

Effector

functions of TH1 cells. CD4+ T cells that differentiate into TH1 cells secrete IFN-gamma;, lymphotoxin (LT) and TNF, and IL-2. IFN-gamma; acts on macrophages to increase phagocytosis and killing

of microbes in phagolysosomes and on B lymphocytes to stimulate production of IgG antibodies that opsonize microbes for phagocytosis. LT and TNF activate neutrophils and stimulate inflammation. IL-2 is

the autocrine growth factor made by this subset of T cells (not shown). APC, antigen-presenting cell (Abbas)

Effector

Functions of Th1 cells-Defense against intracellular pathogens (Macrophage activation, antiviral responses) but also extracellular pathogens (antibodies)

Activation and functions of macrophages in cell-mediated immunity. In cell-mediated immunity, macrophages are activated by CD40L-CD40 interactions and by IFN-gamma; and perform several functions

that kill microbes, stimulate inflammation, and enhance the antigen-presenting capacity of the cells. (Abbas)

Th1 cells

Following T-B cell interactions cytokines are released byactivated T cell-Determines class of antibody that is produced

Th1 cytokine

Selected examples of switched isotypes

in humans are shown

(Abbas) Antibody-mediated opsonization and phagocytosis of microbes. Antibodies of certain IgG subclasses bind to microbes and are then

recognized by Fc receptors on phagocytes. Signals from the Fc receptors promote the phagocytosis of the opsonized microbes and

activate the phagocytes to destroy these microbes.

IgG1 and IgG3 can opsonise

microbe for phagocytosis

(Abbas) Antibody-dependent cell-mediated cytotoxicity. Antibodies of certain IgG subclasses bind to cells (e.g., infected cells), and

the Fc

regions of the bound antibodies are recognized by an Fcgamma receptor on NK cells. The NK cells are activated and kill the antibody-

coated cells.

IgG1 and IgG3 can opsonise

cells for killing by NK cells

(Abbas) Effector functions of TH2 cells. CD4+ T cells that differentiate into TH2 cells secrete IL-4 and IL-5. IL-4 acts on B cells to stimulate production of antibodies that bind to mast cells, such as IgE. IL-4 is also an autocrine growth and differentiation cytokine for TH2 cells. IL-5 activates eosinophils, a response that is important for

defense against helminthic infections.

Th2 response predominates in Helminth

infections-2 billion people infectedmost parasites in intestine, some invade epithelial barrier

and others found

in tissues such as liver, lung.Th2 cytokines lead to high IgE

production and recruitment of mast cells & eosinophils

.•

Parasites such as worms cannot be ingested by phagocytes, instead antibodies coat the parasite and eosinophils

can attack the parasite

through their binding to FcRs. Eosinophils

express FcεR, FcγRs, FcαRs bind to IgE, IgG

and IgA

coated parasites. Eosinophils-major basic

protein and eosinophil

cationic protein-highly toxic to helminths

Parasitic InfectionsEosinophils

attacking a schistosome

larva

Parasitic Infections-IgE

causes Mast cell Degranulation•

IgE

binds to high affinity FcεRI

on tissue mast cells

•

Crosslinkage

of receptor-bound IgE

molecules by antigen induces

degranulation

of mast cells

•

Mast cells located in high numbers in GIT

•

Histamine, lipid mediators lead to gut peristalsis

•

Vasodilation

and increase in vascular permeability, increase in neutrophils/eosinophils

to the site

of infection (chemokines), important in defense against parasitic infections, eosinophil

binds to antibody coated parasite

Th17 cells•

Named Th17 as secrete IL-17

•

Important in defense against certain bacteria and fungi

•

Early Response-leads to recruitment of neutrophils

and macrophages to infected tissues.

•

Induces expression of proinflammatory

cytokines (TNF and IL-6), chemokines

(neutrophil

chemotaxis), matrix metalloproteinases

•

Associated with autoimmune diseases (eg

rheumatoid arthritis, Multiple Sclerosis)

Mechanisms of CTL-mediated lysis of target cells. CTLs kill target cells by two main mechanisms. A. Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes are delivered into the cytoplasm of the

target cells by a perforin-dependent mechanism, and they induce apoptosis. B. FasL is expressed on activated CTLs, engages Fas on the surface of target cells, and induces

apoptosis (Abbas).

Immune synapse between CTLs and a target cell (Abbas)

Learning Outcomes

•

CD8+ cytotoxic

T cells together with which CD4+ effector

T cells are concerned with the elimination of intracellular pathogens?

•

IFN-γ

leads to the differentiation of IgX

(?) secreting B cells

•

Th1 cells lead to the activation of macrophages, what are the other effector

functions of the Th1 cells? What type of

pathogens do Th1 cells eliminate? (intracellular/extracellular?)

•

IL-4 is the signature cytokine of Th2 cells. What are the key roles of Th2 cells in the immune response to pathogens?

•

Describe how CTL kill their target cells?

Effector CD4+ T cellTh1 Th2 Th17

Indicate the Effector

Functions

Fill in this table

Reading Material

•

Parts of Chapters 8 & 9 (Janeway)•

Or

•

Parts of Chapters 10 & 13 (Abbas, Lichtman, Pillai

Cellular and Molecular Immunology)

•

Or •

Alternative Textbook (Humoral

and Cell-Mediated Immunity)