Transcript Lecture 5 T Cell-Mediated Immunity

Lecture 5
Effector Mechanisms
Host
Defense
Innate
Defense
Mechanisms
Inborn independent
of previous
experience
Naturally
acquired
Active
after natural
exposure to a foreign
agent
Passive
placental transfer
Adoptive
immune cells in
colostrum
Active
Specific
immunization
Passive
administration of
preformed antibodies
Adoptive
Bone marrow
transplant
Acquired
Artificially
acquired
Effector Mechanisms
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Antibody-mediated
Neutralizing
 Opsonization
 Complement activation
 Receptor-mediated
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 Antibody-dependent
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cellular cytotoxicity
Cell-mediated
Direct cytotoxicity (induction of apoptosis)
 Cytokines
 Regulatory
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T-cell Mediated Cytotoxicity
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Necrosis
Programmed cell death or apoptosis
Cytokines
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Polypeptides produced by a variety of cell types including T
lymphocytes used for communications between cells.
Cytokine production is triggered by specific receptor binding
and subsequent signal transduction pathways
Cytokine repertoire is dependent on cell type triggered,
receptors present on that cell type.
Cytokines act on cells that possess receptors for them.
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Play role similar to hormones (messengers of the endocrine system)
Hormones usually act at a distance
Cytokines act locally
Play an important role in both innate and adaptive immunity
Properties of cytokines
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Proteins
Low molecular weight
Bind to receptor on either cell which produced it or
another cell
Receptor binding triggers a signal
Signal results in altered pattern of gene expression
Are not antibodies
Lymphocyte Migration, Activation, and Effector
Function Depends on Cell-Adhesion Molecules
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A variety of cell surface polypeptides serve as
receptors to ensure appropriate cell-cell
interactions. These polypeptide include:
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Selectins
Integrins
Immunoglobulin Superfamily
Mucin-like Vascular Addressins
Cytokine nomenclature
 Interleukins
(1-18)
 Interferons (a,b,g)
 Others (common names)
Cytokine -mediated effects
Cell growth
 Cell differentiation
 Cell death
 Induce non-responsiveness to other
cytokines/cells
 Induce responsiveness to other cytokines/cells
 Induce secretion of other cytokines
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How can non-specific cytokines
act specifically?
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Only cells expressing receptors for specific cytokines
can be activated by them
Many cytokines have very short half-lives
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Only cells in close proximity will be activated
High concentrations of cytokines are needed for
activation
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Only cells in close proximity will be activated
May require cell-to cell contact
Cytokines in the immune response
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Alert to
infection.tumor/etc.
Recruit cells to site
Specify type of immune
response
Immune effector phase
Immune downregulation
Immune memory and
resetting the system
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Early mediators (IFNa/b)
Chemokines (MIP-1a)
Early & late mediators
(IL-2, IFNg, IL-4, IL-5)
Down-regulators (IL-10,
TNFg)
Maintenance of
cytokines, etc. (GM-CSF,
IL-3, IL-7, etc.)
Cytokine secretion and biological
activities of TH1 and TH2 Subsets
Type 1
Cell-mediated
Immune response
(intracellular
Organisms)
Type 2
T cell
IL-2
IFN-g
TNF
IL-4
IL-5
Humoral
response
(parasites)
Role of TH1/TH2 balance in determining
disease outcomes
Balance of two subset determines response
to disease
 Leprosy
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Tuberculoid (TH1, CMI response, patient lives)
 Lepromatous (TH2, humoral response, patient
dies)
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Cytokine-related diseases
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Bacterial septic shock
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Blood pressure drops, clots form, hypoglycemia ensues, patient dies
LPS triggers results in TNF release
TNF induces IL-1 which induces IL-6 and IL-8
Bacterial toxic shock and related diseases
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Superantigens trigger large numbers of T cells which release massive amounts
of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell receptors and the MHC class II
molecules on APC’s, bypassing the need for antigen)
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Lymphoid and myeloid cancers
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Some cancer cells secrete cytokines
Chagas’ disease
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Trypanosoma cruzi infection results in sever immune suppression
Depression of IL-2 receptor production
Infectious agents that target cytokines
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Epstein-Barr virus foster the generation of T helper cells
that do not produce IL-2.
EBV produces an analog of IL-10 that favors TH2 cells,
rather than TH1.
Parasites such as tape worms induce high levels of IgE,
an immunoglobulin induced by TH2 cells.
Since TH1 cells mediate inflammation, this may be a
protective ploy to avoid destructive inflammatory
processes.
Immunosuppressive effects of oral
bacteria on immune function
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Impairment of B and T cell function (P. intermedia, P.
asaccharolytica, P. endodontalis, P. melaninogenica)
Production of specific toxins that kill monocytes (A.
actinomycetemcomitans)
Provoke the release of peroxide, prostaglandins and
other mediators capable of inhibiting lymphocyte
function (T. denticola)
Modulate expression of cytokines
Cytokine-inducing components of Grampositive bacteria
Interferon Action
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Viral replication stimulates the infected host cell to
produce interferon.
Interferon induces uninfected cells to
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produce antiviral proteins that prevent translation of viral
mRNA
degrade viral nucleic acid
Viral replication is blocked in uninfected cells
Interferon Action
Therapeutic uses of cytokines
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Modulation of TH activation
Interfere with receptor function
Interfere with cytokine
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Make it unable to bind to receptor
Make it unable to act
Examples of therapeutic uses
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Soluble T-cell receptor
Anti-IL-2R
Interleukin analogs which bind receptor, but do not
trigger activation (ties up receptor)
Toxins conjugated to cytokines which kill activated Tcells
Administration of cytokines to enhance immunity (side
effects/ short half lives)
Allergies
Summary
Effector cells and antibodies play critical roles in
almost all adaptive immune responses
 Antigen-presenting cells play critical role in
processing and presenting antigen to T cells
 Cytokines are released by a variety of cell types
and regulate a variety of biological effects
 T-cell mediated cell death is largely via apoptosis
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What’s the bottom line?
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Innate immunity is a function of anatomical, mechanical and biochemical
factors.
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Adaptive immune system recognizes foreign agents via receptors and develops
memory.
Triggering the adaptive immune response results in activated T cells and
antibodies specific for the substance (antigen) that triggered it.
Antibodies react with antigen
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No requirement for prior exposure/memory
Biochemical response may involve pattern recognition
Lacks the specificity of the adaptive immune system
Block or neutralize
Activate complement system
Bind to Fc receptors on cells providing specificity to the effector activity of those cells
Activated T cells
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Cytotoxic against foreign agent (tumor cell, transplant, virus-infected cell)
May influence other cells (Helper/Suppressor T cells, cytokines)