Transcript Presentation

The life history of T lymphocytes
Precursors mature in the thymus
Naïve CD4+ and CD8+ T cells enter the circulation
Naïve T cells circulate through lymph nodes
and find antigens
Clonal expansion;
differentiation into effector and memory cells
Effector T cells migrate to sites of infection
Eradication of infection
Lecture outline
• Properties and functions of subsets of
CD4+ effector T cells; functions of
cytokines
• Activation and functions of CTLs
• Cell-mediated immunity: T cell-mediated
defense against intracellular microbes
• Migration of T cells; activation of
phagocytes and other leukocytes by
effector T cells
Functions of CD4 helper T cells, the master controllers of
immune responses, are mediated by cytokines
Discovery of Th1 and Th2 subsets
• Immune responses to mycobacteria and
helminths are very different but CD4+ T
cells are required for both
– How can the “same” CD4+ T cells trigger such
distinct reactions?
Discovery of Th1 and Th2 subsets
• Immune responses to mycobacteria and
helminths are very different but CD4+ T
cells are required for both
– How can the “same” CD4+ T cells trigger such
distinct reactions?
• Hypothesis: CD4+ T cells consist of
subpopulations that mediate different
responses
• Identification of mouse CD4+ Th1, Th2
clones that produce distinct cytokines
The discovery of the Th17 subset
• The first two subsets were identified on
the basis of distinct cytokine profiles
and were called type 1 and type 2 helper
cells (Th1 and Th2)
• Many inflammatory diseases (mouse
models first) thought to be caused by
Th1 cells were not prevented by
eliminating Th1 cells or their cytokines
• Led to the discovery of the Th17 subset
(annoying nomenclature!)
CD4+ TH subsets
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011
c Elsevier
CD4+ T cell subsets: definitions and
general properties
• Populations of CD4+ T cells that make
restricted and non-overlapping sets of
cytokines
– Early after activation, T cells can produce
multiple cytokines
– Progressive activation leads to “polarization”:
production of selected cytokines
• Distinct functions, migration properties,
roles in disease
Effector functions of TH1 Cells
TH1 cells stimulate
phagocyte-dependent
host defense, the
defense mechanism
that works against
most bacteria and
viruses that enter
tissues and are
ingested by
phagocytes
Development of TH1 cells
Th1 cells develop in
response to microbes
that activate dendritic
cells and macrophages
(most ingested bacteria
and viruses).
Effector functions of TH2 Cells
Th2 cells combat
helminths, provide
defense at
mucosal barriers
(“barrier
immunity”), and
are involved in
allergic reactions.
IgG4 (human),
IgG1 (mouse)
Antibody
production
Development of TH2 cells
Th2 cells develop in
response to organisms
that induce the local
production of IL-4
and do not activate
macrophages and
dendritic cells
strongly.
Effector functions of TH17 Cells
Chemokines,
TNF, IL-1, CSF
s
Inflammation
Th17 cells combat
extracellular bacteria
and fungi.
These microbes
activate DCs to
produce Th17-inducing
cytokines.
Th17 cells are also
involved in many
inflammatory
diseases.
Helper T cell subsets
• CD4+ helper T cells orchestrate specialized
immune responses to different types of microbes
• The development of different Th subsets is
driven by cytokines produced by APCs and other
cells when naïve CD4 cells are being activated
– Each subset is induced by the types of microbes that
subset is designed to combat
• Once a subset is generated, it makes cytokines
that induce more of the same and shut off the
others --> polarization of the immune response
towards increasing specialization (a feature of
adaptive immunity)
Genetic proof for the importance of
different T cell subsets in humans
• Mutations affecting IL-12/IFN-g cytokines
or receptors  defective Th1 responses 
atypical mycobacterial infections
• Mutations affecting Th17 development or
IL-17  mucocutaneous candidiasis and
bacterial abscesses (“Job’s syndrome”)
16
Roles of T cell subsets in disease
• Th1: autoimmune and inflammatory
diseases (IBD?, MS?, RA?); tissue
damage in infections (e.g. Tb)
– Activation of macrophages, CTL responses;
production of injurious antibodies
• Th2: allergies (e.g. asthma)
– Stimulation of IgE responses, activation of
eosinophils
• Th17: inflammatory diseases (MS, IBD,
RA, psoriasis)
– Recruitment of leukocytes (inflammation)
The balance of Th1 and Th2 responses determines the
outcome of some infections
Cytotoxic (cytolytic) T lymphocytes (CTLs)
• CD8+ CD4- cells that recognize class I MHCassociated peptides derived from cytoplasmic
protein antigens in any nucleated cell
• Effector functions:
– Killing of infected cells (microbes in cytoplasm),
tumor cells (tumor antigens in cytoplasm)
– Secretion of IFN-g --> activation of
macrophages (when microbes escape into
cytoplasm and antigens enter class I MHC
pathway)
Mechanisms of killing of infected cells by CD8+ CTLs
CTLs “inject” their granule
contents into target cells
through membrane “pores”;
major granule contents are
enzymes that activate
caspases and induce
apoptotic death of the
target cells, i.e. help the
target cells to commit
suicide
Cell-mediated immunity against the intracellular
bacterium Listeria monocytogenes
In defense against
intracellular microbes,T cells
provide specificity and
activate phagocytes,
phagocytes kill the bacteria
Cell-mediated immunity (CMI)
• Defense against intracellular microbes
• Mediated by T lymphocytes
– CD4+ T cells activate phagocytes
(macrophages and neutrophils), eosinophils
– CD8+ T cells kill infected cells, activate
macrophages
– T cell-mediated leukocyte recruitment and
macrophage activation also cause delayed
type hypersensitivity (DTH), which may have
injurious effects
Stages in the development of T cell responses: induction
Stages in the development of T cell responses:
effector phase
Migration of naïve and effector T cells
Naïve T cells migrate preferentially to secondary lymphoid organs,
previously activated T cells to sites of infection and inflammation.
Cell migration is regulated by adhesion molecules and chemokines.
Retention of effector T cells at sites of infection
T cells are retained
at sites of antigen
recognition in
peripheral tissues,
because antigen
recognition stimulates
expression of highaffinity adhesion
receptors (integrins) that
bind to extracellular
matrix
Determinants of migration of naïve
and effector T cells
• Naïve T cells:
– L-selectin: binds to HEV in lymph nodes
– CCR7: recognizes chemokines made in
peripheral lymphoid organs (lymph nodes,
spleen, etc)
• Effector T cells:
– Ligands for E- and P-selectins: bind to
endothelium at sites of infection
– Various chemokine receptors: recognize
chemokines made at sites of infection
– Increased expression of integrins: bind to
extracellular matrix proteins
Functions of CD4+ T cells
are mediated by CD40ligand and cytokines
Mutations of CD40L (or
CD40) are the cause of a
human disease
associated with defects in
antibody responses and
CMI
Requirement for cell-cell
contact ensures T cells
recognize macrophages or
B cells with the relevant
antigen
Therapeutic applications:
inhibit abnormal immune
responses, graft rejection
with anti-CD40L antibody
Activation of macrophages by T cells
T cells (via CD40L, IFNg) stimulate production of microbicidal
substances in macrophages -- make phagocytes better able to kill
what they eat.
Functions of activated macrophages in CMI
Macrophage response
Role in CMI
Production of reactive oxygen
species, nitric oxide,
lysosomal enzymes
Killing of microbes in
phagolysosomes (main
effector function)
Secretion of cytokines (TNF,
IL-1, chemokines, others)
Leukocyte recruitment
(inflammation)
Increased expression of
B7 costimulators, MHC
molecules
Increased T cell
activation (adaptive
immunity)
Macrophages are activated by TLR recognition of
microbes as part of innate immunity; T cells activate
them more
Classical and alternative macrophage activation
The life history of T lymphocytes
Precursors mature in the thymus
Naïve CD4+ and CD8+ T cells enter the circulation
Naïve T cells circulate through lymph nodes
and find antigens
Clonal expansion;
differentiation into effector and memory cells
Effector T cells migrate to sites of infection
Eradication of infection