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Helper T cells and cytokines
Cytokines
 Cytokines are secreted proteins that regulate cellular activities. They bind to
cell surface receptors and trigger intra-cellular signalling pathways. About
100 cytokines have been identified, including the interleukins (IL-1, IL-2, IL3, etc.), the tumour necrosis factors (TNF- and TNF- ), the interferons (IFN, IFN-, IFN-), colony stimulating factors (G-CSF, M-CSF, GM-CSF), and
chemokines. Many cell type produce cytokines and respond to them.

Cytokines produced by T helper cells are particularly important in regulating
immune responses. Different Th cells preferentially produce different
cytokines that drive different types of immune response. Th1 cells produce
cytokines like IFN- that activates macrophages, and IL-2 that activates T
cells (including Tc cells). Thus, Th1 cells promote cell-mediated immunity;
they also induce B cells to produce IgG antibodies (subclasses IgG1, IgG2,
IgG3). Th2 cells produce cytokines like IL-4 and IL-10 that principally induce
B cell activation and Th2 cells promote the production of all antibody isotypes
(IgG1-4, IgE and IgA). Furthermore, Th1 and Th2 cells tend to be mutually
inhibitory, with IFN- inhibiting Th2 activation, and IL-10 inhibiting Th1
activation. Naïve T cells have the capacity to differentiate into either Th1 or
Th2 cells, and are therefore termed Th0 cells. Th0 differentiation into Th1
cells is promoted by IL-12, whereas IL-4 promotes differentiation to Th2.
Lymphocyte activation and the generation of antibody responses
 Antigens are transported from sites of infection to lymphoid tissues - eg. to
draining lymph nodes via the afferent lymphatics. Some antigen is carried
free in the afferent lymph, whereas some is taken up in the infected tissues
by dendritic cells (DC), which are activated to migrate into the lymphatics and
thence to the draining lymph nodes.

As described in the session on ‘T cell-mediated immunity’, the DCs process
the protein antigens that they take up and present antigen peptides on their
surface bound to HLA class II molecules. Within the lymph node, Th cells
expressing TCR specific for the peptides presented by the DCs are activated
by their surface molecule interactions with the DCs, and also by cytokines
released by the DCs (eg. IL-1).

The soluble antigens that enter the lymph node are bound by B cells with
surface immunoglobulins specific for epitopes of the antigens. The B cells
then internalise the sIg-bound antigens and process the antigenic proteins to
generate peptides that are presented on the surface of the B cells bound to
HLA class II proteins, i.e. the B cells then function as antigen presenting cells.
Thus, the T cells that were activated following recognition of peptides
presented by the DCs can now interact with copies of these peptides on the
surface of B cells. This Th-B cell interaction activates the B cells, with the
help of cytokines secreted by the Th cells (eg. IL-4). Some of the activated B
cells differentiate into plasma cells that secrete antibodies specific for the
stimulating antigens.

The main function of secondary lymphoid tissues is to provide an optimal
environmental for the antigen-specific clonal selection and activation of T and
B lymphocytes: this could not happen as efficiently within the infected tissues
themselves. This is why antigens are carried from sites of infection to
secondary lymphoid tissues where the relatively few lymphocytes with
receptors specific for any particular antigen are to be found amongst the
millions that populate lymphoid tissues. The activation of antigen-specific Th
cells by DCs, and the activation of antigen-specific B cells by the Th cells,
takes place within the paracortex of lymph nodes. The activated B cells then
migrate to the lymphoid follicles where they undergo rapid proliferation to
form germinal centres (thus increasing the size of the response). The B cells
then undergo further maturation processes: selection of B cells with the
highest affinity and specificity for the antigens; Ig class switching that
increases the range of defensive functions; formation of plasma cells and
memory cells.

The activated T and B cells then leave the lymph nodes via the efferent
lymphatics and re-enter the blood stream. Tissue homing of the activated
lymphocytes back to the sites of infection is determined by their expression of
particular adhesion molecules (eg. integrins) and chemokine receptors.

Th2 cells particularly promote B cells to produce IgE because IL-4 stimulates
Ig class switching to IgE. This sensitises mast cells that bind the IgE to their
high affinity FcR. Th2 cells also produce IL-5 that stimulates eosinophil
differentiation (and eosinophils also bind to IgE). IgE, eosinophils and mast
cells are particularly important in immune responses to large parasites (i.e.
parasitic worms), but this same combination of components also react to noninfective environmental antigens termed allergens, thereby generating tissue
damaging atopic allergies.
Cell-mediated immunity and granulomatous inflammation
 When macrophages present HLA class II-bound antigen peptides that are
recognised by Th1 cells, IFN- secreted by the Th1 cells further activates the
phagocytotic and digestive activity of the macrophages.

Some microbes have evasion mechanism to resist destruction by
macrophages – important examples are the mycobacteria that cause
tuberculosis and leprosy, which can survive and replicate inside macrophages
that have phagocytosed them.

Chronic activation of Th1 cells by macrophages infected by mycobacteria
leads to increasing lymphocytic infiltration of the tissues, and to chronic
macrophage activation resulting in granuloma formation. Leakage of
digestive enzymes form the macrophages into the surrounding tissues also
causes tissue destruction. This can occur in lung tissue infected by M.
tuberculosis.

Particularly poor control of mycobacterial infection can occur if there is
activation of Th2 cells rather than Th1 cells: this is seen in leprosy caused by
skin infection by M. leprae. A Th1 response helps to destroy the
mycobacteria by IFN- activating macrophages and thus controlling the
infection, but this also generates inflammatory tissue damage – this occurs in
tuberculoid leprosy. A Th2 response mainly activates B cells to produce
antibodies, but these are not useful against the mycobacteria inside
macrophages; furthermore Th2 cells will tend to inhibit a protective Th1
ressponse. In this case the mycobacteria can proliferate and spread through
the tissues causing severe tissue damage – this is the situation in
lepromatous leprosy.
Recommended reading:
Todd I, Spickett G (2005) Lecture Notes: Immunology. 5th edition. Blackwell
Publishing. Chapters 3 and 4. OR
Todd I, Spickett G (April 2010) Lecture Notes: Immunology. 6th edition.
Wiley/Blackwell. Chapters 3 and 4.