Effector Mechanisms of Cell-Mediated Immunity

1
Effector Mechanisms of Cell-Mediated Immunity
2
Cell Mediated Immunity

• Historically, immunologist have divided adaptive
  immunity into namely
• CMI, which can be adoptively transferred only by
  viable T lymphocytes and
• humoral immunity, which can be adoptively
  transferred with serum containing antibodies.

3
Cell Mediated Immunity

• General responses by CMI, include
• Facilitate innate immune response to bacteria
• Anti-viral
• Anti-fungal
• Anti-tumor
• Transplantation rejection

4
Cell Mediated Immunity

• Many microbes have developed mechanisms that
  enable them to survive and even replicate within
  phagocytes, so the innate immunity is unable to
  eradicate infections by such microbes.
• In CMI against phagocytosed microbes, the
  specificity of the response is due to T cells
  but the actual effector function is mediated by
  the phagocytes.

5

• CD4 TH1 cells and CD8 T cells recognize class
  II MHC-associated or class I MHC-associated
  peptide antigens of phagocytosed microbes,
  respectively, and produce cytokines (IFN-g, TNF)
  that activate the phagocytes to kill the microbes
  and stimulate inflammation.

6
Listeria monocytogenes

• Protection to Listeria infection can be
  adoptively transferred by infusing T cells from
  an infected mouse into a naïve mouse.
• This experiment was performed in 1950 by George
  Mackaness.

7
Delayed-type Hypersensitivity

• There is a hypersensitivity condition that also
  demonstrates the T cell activation of
  macrophages.
• Delayed-type hypersensitivity (DTH) is
  responsible for tissue injury due to Mf and
  pro-inflammatory cytokine release.
• DTH will be discussed in the hypersensitivity
  lectures.

8
DTH
Fig. 13-12
9
DTH
Fig. 13-13
10
Cell Mediated Immunity

• In a classical sense of CMI, CD8 lymphocytes
  kill non-phagocytic cells infected with microbes.

11
Cell Mediated Immunity

• CMI in response to helminthic parasites is
  mediated by TH2 cells that stimulate the
  production of IgE and activation of eosinophils.

12
Cell Mediated Immunity

• Cell-mediated immune responses consist of the
  development of effector T cells from naïve cell
  in peripheral lymphoid organs, migration of these
  effector T cells and other leukocytes to sites of
  infection, through
• either cytokine-mediated activation of leukocytes
  to destroy microbes or
• direct killing of infected cells.

13
Cell Mediated Immunity

• Keep in mind that naïve T cells do not produce
  effector cytokines or the molecules to kill other
  cells.
• The development of the effector T cells of CMI
  involves the sequence of antigen recognition,
  clonal expansion, and differentiation as we
  have previously defined.

14
Cell Mediated Immunity

• CD4 cells may differentiate into subsets of
  effector cells that produce distinct sets of
  cytokines and therefore distinct effector
  functions.
• These effector cell have been previously defined
  by us as TH1 and TH2.

15
TH1 and TH2

• The control of TH polarization is through the
  dendritic cell.
• DC1 polarizes TH1 through IL-12
• DC2 polarizes TH2 through IL-4
• DC1 function appears to be through Toll-like
  receptors that bind bacterial DNA motifs
  (reviewed p 282-283).
• DC2 function appears to be though increased
  levels of cAMP.

16
Toll-like receptors

• Toll-like receptors (TLRs) are a family of
  pattern recognition receptors that are activated
  by specific components of microbes and certain
  host molecules.
• INNATE RESPONOSE They constitute the first line
  of defense against many pathogens and play a
  crucial role in the function of the innate immune
  system.
• ADAPTIVE RESPONSE TLRs were observed to
  influence the development of adaptive immune
  responses, through activating antigen-presenting
  cells, DC1.

17
Toll-like receptors (TLR)

• TLRs are type I transmembrane proteins
• TLR3 recognizes dsRNA, a viral product
• TLR9 recognizes unmethylated CpG motifs
  frequently found in the genome of bacteria and
  viruses, but not vertebrates.
• TLR7 recognizes small synthetic immune modifiers
  including imiquimod, R-848, loxoribine, and
  bropirimine, all of which are already applied or
  promising for clinical use against viral
  infections and cancers.

18
Toll-like receptors (TLR)

• Plasmacytoid dendritic cells express TLR7 and
  TLR9, and respond to TLR7 and TLR9 ligands by
  producing a large amount of IFN-a.
• TLR3, TLR7 and TLR9 play an important role in
  detecting and combating viral infections.

19
(No Transcript)
20
TH1 vs TH2
21
TH1

• TH1
• The polarization to TH1 can be stimulated by
  intracellular bacteria and viruses that infect
  macrophages.
• A second pathway already described is microbe
  engagement of TLR.
• A common feature of these infections is that they
  elicit innate immune reactions with the
  production of IL-12.
• Enhancement of IL-12 production is through TH
  CD40L with APC CD40.

22
TH1

• TH1
• IL-12 binds to CD4 cells and activates STAT4, a
  transcriptional factor that promotes TH1
  polarization.
• IFN-g also induces T-bet, a transcriptional
  factor that enhances the TH1 polarization.
• IFN-g stimulates further production of IL-12 by
  APCs and IL-12r on the lymphocyte.

23
TH1
24
TH1 and TH2

• TH2
• The differentiation of antigen stimulated T cells
  to TH2 is dependent on IL-4.
• IL-4 activates the transcriptional factor STAT6.
• GATA-3 transcriptional factor, increases due to
  antigen presentation and enhances the
  transcription of TH2 cytokine gene transcription.

25
Fig. 13-7
26
CTL-Killing
27
Effector Mechanisms T-cells

• Chapter 6
• Accessory Molecules of T-cells.
• Adhesion molecules.

28
Integrin

• A concept has evolved suggesting that T cells
  initiate antigen-independent adhesive
  interactions with apposing cells to scan the
  surface for specific antigen, followed by even
  stronger antigen-dependent adhesive interactions
  that would allow for specific activation of
  T-cell proliferation, cytokine production, or the
  delivery of a lethal hit to the target cell.

29
Integrins

• Integrins are important for many different
  physiologic processes, including embryogenesis,
  thrombosis, wound healing, tumorigenesis and
  immune responses.
• The integrin supergene family consists of a
  number of cell surface ab heterodimers.
• The a and b chains are type I transmembrane
  glycoproteins with a single hydrophobic
  transmembrane domain, a short cytoplasmic tail,
  and an extracellular domain that associates
  noncovalently to form the heterodimer.

30
Integrins
Page 120
31
(No Transcript)
32
Integrins

• In the immune system, the most important
  integrins, those of the b1, b2, and b7
  subfamilies, participate in T-cell migration and
  provide stimulatory signals for T-cell
  proliferation and effector functions.

33
Integrins

• T-cell migration into tissues requires T-cell
  binding to and extravasation through endothelium,
  an integrin-dependent process.
• Current models propose that chemokines deliver
  the critical biochemical signals that promote
  endothelial binding through the upregulation of
  integrin avidity on the T cell.

34
Integrins

• Integrin-mediated events are also critical for T
  cells that participate in immune surveillance.
• As resting T cells circulate through the blood,
  they adhere specifically to the specialized
  endothelium of the postcapillary venules of
  secondary lymphoid organs or HEVs and extravasate
  from the bloodstream into the underlying
  secondary lymphoid tissues.

35
Integrins

• How do the adhesion molecules regulate their
  binding activity to allow both the attachment as
  well as detachment characteristics required for
  transmigration into and out of the inflamed
  endothelium and draining lymph nodes?
• Lymphocytes have solved this problem by tightly
  regulating the affinity and avidity of integrin
  receptors.

36
Integrins
37
Integrins

• These conformational changes are dependent on
  the presence of specific divalent cations, which
  are bound by the extracellular domains of
  integrins.
• Replacement of bound Ca2 with Mg2 for b2
  integrins or Mn2 for b1 integrins results in
  increased receptor affinity for their ligands

38
Integrins
39
(No Transcript)