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Cell-cell interactions in immune responses. Jennifer Nyland, PhD Office: Bldg#1, Room B10 Phone: 733-1586 Email: jnyland@uscmed.sc.edu. Teaching objectives. To discuss the central role of Th cells in immune responses

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cell cell interactions in immune responses

Cell-cell interactions inimmune responses

Jennifer Nyland, PhD

Office: Bldg#1, Room B10

Phone: 733-1586

Email: jnyland@uscmed.sc.edu

teaching objectives
Teaching objectives
  • To discuss the central role of Th cells in immune responses
  • To describe the cell-cell interactions which occur in 1) Ab responses to T-dependent Ag, 2) generation of CTL, 3) activation of macrophages and NK cells
  • To discuss responses to T-independent Ag
  • To discuss mechanisms of killing by CTL and macrophages
cell cell interactions
Cell-cell interactions
  • Immune cells interact in two ways
    • Direct contact between cells
    • Cytokine signaling acting in autocrine or paracrine fashion
central role of th cells

TCR

Central role of Th cells

Ag

Th cell

T0 cell

B cell

K cell

Macrophage

  • Type of immune response:
    • B activation or CTL generation
  • Proliferation of effector cells
  • Enhance functional activities of other cells

Eosinophil

Cytokines

MHC

NK cell

APC

Cytokines

subpopulations of th cells
Subpopulations of Th cells

preTh

Th0

Th1

Th2

Th17

IFN-γ, IL-2

IL-12

  • Subpopulations based on cytokine profiles
    • Th0, Th1, Th2, Th17
  • Differentiation determined by cytokines

IL-4

IL-2

IL-4, IL-5,

IL-6, IL-10

IFN-γ, IL-2,

IL-4, IL-5,

IL-10

IL-1, 6, 23

IL-17

subpopulations of th cells6
Subpopulations of Th cells

Th1

Th2

B cell

  • Th1 cytokines
    • Activate macrophages
    • Enhance generation of CTL
    • inflammation
  • Th2 cytokines
    • Activate B cells
    • Activate granulocytes
    • Ab-mediated immune response

Macrophage

IFN-γ inhibits prolif

IL-10 inhib productn

IL-10

IL-5

IL-6

IL-4

Eosinophil

IFN-γ

IL-2

Activates

Activates

Mast cell

Ab production

subpopulations of th cells7
Subpopulations of Th cells

Th1

Th2

B cell

  • Regulation
    • Ag
    • IFN-γ inhibits proliferation of Th2 cells & differentiation of Th17
    • IL-10 inhibits production of IFN-γ
    • IL-4 inhibits production of Th1 & differentiation of Th17

Macrophage

IFN-γ inhibits prolif

IL-10 inhib productn

IL-10

IL-5

IL-6

IL-4

Eosinophil

IFN-γ

IL-2

Activates

Activates

Mast cell

Ab production

cell cell interactions in ab responses

Cell-cell interactions inAb responses

Responses to exogenous Ag

T-dependent Ag

hapten carrier effect
Hapten-carrier effect
  • Studies on Ab response to hapten-carrier conjugates show
    • Both Ts and Bs required for Ab production
  • Th cells recognize carrier determinants
  • Bs recognize haptenic determinants
  • Interactions are class II self MHC restricted
  • Bs function in Ag recognition and presentation
mechanism of hapten carrier effect
Mechanism of hapten-carrier effect

Ag

Ag

CD40

BCR

BCR

MHC

MHC

B cell

B cell

TCR

Thcell

1.

  • Hapten recognized by BCR = signal 1
  • Hapten-carrier endocytosed and processed
  • Carrier determinants presented in context of MHC class II to Th2 cells

Hapten binds BCR

Endocytosed

Ag presented

CD28

CD80/86

2. CD80 expressed

mechanism of hapten carrier effect11
Mechanism of hapten-carrier effect

Ag

BCR

BCR

BCR

BCR

MHC

B cell

B cell

B cell

B cell

TCR

Th cell

  • Activated Th2 produce cytokines and CD40L
  • CD40L interacts with CD40 = signal 2
  • Cytokines drive proliferation and differentiation of Bs

CD28

CD80/86

CD40L

4.

Cytokine binds R

CD40L binds CD40

Bs activation

3.

5.

Th activated,

express CD40L, cytokine release

B cell proliferate, differentiate, secrete Ig

cytokines

cell cell interactions in 1 ab response
Cell-cell interactions in 1° Ab response

Ag

Ag

1.

BCR

Th primed

by APC

MHC

B cell

TCR

TCR

Th cell

Th cell

  • Bs are not best APC in 1° Ab response
    • DC and macrophage
  • Th cells can be primed by other APC before interaction with Bs

Th signals B

Bs proliferate, differentiate, secrete Ig

2.

CD28

CD80/86

MHC

APC

CD28

CD80/86

cell cell interactions in 2 ab response
Cell-cell interactions in 2° Ab response
  • Memory Bs and memory Ts created during 1° response
  • Bs have high affinity Ig receptor
    • Can take up Ag at lower concentrations than other APCs that lack Ig R
  • Memory Ts more easily activated than naïve
  • B-T interaction is sufficient to generate 2° Ab response
cytokines and class switching
Cytokines and class switching
  • Th cell cytokines stimulate B cell proliferation and differentiation
  • Cytokines also regulate the class of Ab
cell cell interactions in ab responses15

Cell-cell interactions inAb responses

Responses to exogenous Ag

T-independent Ag

cell cell interactions in response to t independent ag
Cell-cell interactions in response toT-independent Ag
  • Cell-cell interactions do not occur
  • Activation of Bs without class II self MHC-restricted T help
  • Polymeric nature of these Ags allows for cross-linking of Ag receptors on Bs
  • No 2° response, affinity maturation, or switch
  • Response dominated by CD5+ Bs
cd5 b cells
CD5+ B cells
  • CD5+ Bs (B1 cells)
    • Distinct from conventional Bs (B2 cells)
    • First to appear in ontogeny
    • Express surface IgM, little or no IgD
    • Produce IgM from minimally mutated germline
    • Ab are low affinity and polyreactive
    • Account for most of IgM in adult serum
cd5 b cells18
CD5+ B cells
  • Properties (continued)
    • Do not develop into memory Bs
    • Self-renewing: do not continue to arise from bone marrow like conventional Bs
    • reside in peripheral tissues
    • Predominant Bs in peritoneal cavity
  • Significance
    • Major defense against pathogens with polysaccharide in cell wall
    • Individuals with T defects can still resist many bacterial infections
cell cell interactions in cell mediated immune response generation of ctl

Cell-cell interactions incell-mediated immune response:Generation of CTL

Responses to endogenous Ag in cytosol

Killing of virus-infected and transformed cells

cytotoxic t cells
Cytotoxic T cells
  • CTLs are not fully mature when exit thymus
    • TCR recognizes Ag in MHC context
    • Cannot kill
    • Must differentiate to fully active CTL
    • Therefore, are “pre-CTL”
generation of ctl

1.

Generation of CTL

Ag

Stimulator cell presents Ag in MHC class I to CD8+ pre-CTL

stimulator

CD80/86

MHC

Class I

CD28

  • Differentiate in response to:
    • Specific Ag in MHC
    • Cytokines from Th1 Ts

CD4+

Th cell

MHC

Class II

TCR

Ag

APC

TCR

3.

CD8+

pre-CTL

2.

Pre-CTL differentiates to functional CTL

cytokines

Th releases IFN-γ, IL-2

APC presents Ag in MHC II to CD4+ Th cell

features of ctl
Features of CTL
  • Ag specific
    • Target must bear the same Ag in MHC class I as the stimulator cell
  • Requires cell contact
    • Ensures that nearby cells are not killed
  • CTLs are capable of killing many targets
    • They are not “damaged” when they kill a target
mechanisms of ctl killing
Mechanisms of CTL killing
  • Fas and TNF-mediated killing
    • FasL on CTL binds FasR
    • TNF secreted by CTL binds TNFR on target
    • L binding trimerizes R
    • R with death domain activates caspases to signal apoptosis
mechanisms of ctl killing24
Mechanisms of CTL killing
  • CTL granule-mediated killing
    • perforin & granzymes released from CTL granules
    • Perforin polymerizes and forms channels in membrane
    • Granzymes (serine proteases) enter through channel, activate caspases
cell cell interactions in cell mediated immune response activation of macrophages

Cell-cell interactions in cell-mediated immune response: activation of macrophages

Responses to endogenous Ag in vesicles

Killing of intracellular pathogens in vesicles

central role of macrophage in specific immune response
Central role of macrophage inspecific immune response

Macrophage

Macrophage

Macrophage

  • Initial defense
    • Innate, nonspecific immune response
  • Ag presentation
    • Activation of Th
  • Effector functions
    • Cytokine production
    • Anti-microbial
    • Anti-tumor

Infecting

agent

Ag presentation

Activated macrophage

TCR

MHC

Class II

T cell

cytokines

Ag

Activate

Cytokines

Anti-microbial

Anti-tumor

lymphokines

effector function of activated macrophages
Effector function of activated macrophages
  • Pneumocystis carinii
    • Extracellular fungal pathogen
    • Controlled by activated macrophage
    • In AIDS patients infection commonly causes death
  • Mycobacterium tuberculosis
    • Intracellular pathogen, resides in vesicles
    • Not killed unless macrophages are activated
    • Again, problem for AIDS patients