Download Classes of effector CD4 + T cells Development of Th1 cells

EFFECTOR FUNCTIONS OF HELPER
T-LYMPHOCYTES
Phases of T cell responses
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Naive helper T cells encounter antigen during their
recirculation through secondary lymphoid organs
Classes of effector CD4+ T cells
Differentiation of Th subsets from
naïve CD4+ T cells: general principles I.
• Different subsets develop from the same naïve CD4+ T cells.
• Cytokines produced at the site of antigen recognition drive
differentiation into one or the other subset.
• The cytokines that drive the development of CD4+ T cell
subsets are produced by APCs (primarily dendritic cells and
macrophages) and other immune cells (such as NK cells and
basophils or mast cells) present in the lymphoid organ where
the immune response is initiated.
Differentiation of Th subsets from
naïve CD4+ T cells: general principles II.
• Stimuli other than cytokines may also influence the pattern
of helper T cell differentiation.
• Differentiation of each subset is induced by the types of
microbes that the subset is best able to combat.
• Commitment to each subset is driven by transcription
factors.
• Each subset of differentiated effector cells produces
cytokines that promote its own development and may
suppress the development of the other subsets.
Classes of effector CD4 + T cells
Molecular events in follicular helper T cell generation
Diversity of follicular helper T cells (Tfh)
Follicular helper T cells (Tfh)
• Some effector T cells express the chemokine receptor CXCR5,
migrate to lymphoid follicles, and help B cells
(isotype switching, affinity maturation)
• Characteristics of Tfh:
– Surface expression of CXCR5, ICOS
– Transcription factor: BCL-6
– Cytokines secreted: IL-21 + IL-4 or IFNγ (or IL-17?)
Sequence of events in the reactions of effector CD4+ T cells
in the peripheral tissues
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Classes of effector CD4 + T cells
Development of Th1 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Functions of Th1 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Effector functions of Th1 cells
Activation
Killing
Proliferation
Feed back
Entry to tissue Recruitment
Macrophage activation by Th1 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Th1 cells
• Th1 differentiation is driven mainly by the cytokines IL-12 and
IFN-γ and occurs in response to microbes that infect macrophages.
• IFN-γ and IL-12 stimulate Th1 differentiation by activating the
transcription factors T-bet, STAT1, and STAT4.
• The principal function of Th1 cells is to activate macrophages
to ingest and destroy microbes.
- Classical macrophage activation
- Enhance of MHC-associated antigen presentation
Classes of effector CD4 + T cells
Development of Th2 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Functions of Th2 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Classical and alternative macrophage activation
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Th2 cells
• Th2 differentiation is stimulated by the cytokine IL-4 and occurs
in response to helminths and allergens.
• IL-4 stimulates Th2 development by activating the transcription
factor STAT6, which, together with TCR signals, induces expression
of GATA-3.
• Th2 cells stimulate IgE-, mast cell- and eosinophil-mediated
reactions that serve to eradicate helminthic infections.
- Activation of mast cells and eosinophils
- Host defense at mucosal barriers
- Alternative macrophage activation
Classes of effector CD4 + T cells
Development of Th17 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Functions of Th17 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Th17 cells
• The development of Th17 cells is stimulated by proinflammatory
cytokines produced in response to bacteria and fungi.
• The development of Th17 cells is dependent on the transcription
factors RORγt and STAT3.
• The principal effector function of Th17 cells is to help the destroy
of extracellular bacteria and fungi, mainly by inducing neutrophilic
inflammation.
• Th1 and Th17 cells function cooperatively in phagocyte-mediated
elimination of microbes in cell-mediated immunity.
• Th17 cells contribute to the pathogenesis of many inflammatory
diseases. (MS, IBD, RA, psoriasis)
Functional classes of effector CD4 T cells
Genetic proof for the importance of different
T cell subsets in humans
• Mutations affecting IL-12/IFN-γ cytokines or
receptors → defective Th1 responses → atypical
mycobacterial infections
• Mutations affecting Th17 development or IL-17 →
mucocutaneous candidiasis and bacterial abscesses
(Job’s syndrome)