Immune cells in the lung
Nunja C. Habel-Ungewitter & Sabine Bartel
12.11.14
immunity
• from immunis, Latin for "exempt“
• capability of the body to resist harmful
microbes from entering it
• Immunity involves both specific and nonspecific components
immunity
Innate vs. adaptive immunity
Innate immune system
Adaptive immune system
non-specific response
pathogen and antigen specific response
highly conserved pattern
recognition receptors (PRRs)
immediate maximal response
(hours)
highly specialized, variable receptors
lag time between exposure and maximal
response (days)
cell-mediated and humoral
components
no immunological memory
cell-mediated and humoral components
found in nearly all forms of life
found only in jawed vertebrates
immunological memory
Adaptive immune response
Innate and adaptive immunity
Innate
• skin/mucosal tissues
• Complement System
• Antimicrobial Peptides
• Phagocytes (Macrophages,
PMNs, Monocytes, DCs)
• Adaptive Immune System
Activation
Acquired (Adaptive)
• B Lymphocytes
-Antibodies
• T Lymphocytes
-Cytotoxicity
-Cytokine Secretion
-B cell Activation
The immune system: overview
Antigen presentation
Complement system
Complement system
"Janeway's Immunobiology"
Lymphatic organs
Tonsils and adenoids
Lymph nodes
Lymphatic vessels
Thymus
Lymph nodes
Spleen
Peyer’s patches
Appendix
Lymph nodes
Bone marrow
Primary lymphatic organs:
Lymphatic vessels
generation of lymphocytes
bone marrow, thymus
Secondary lymphatic organs:
initiation of adaptive immune responses
lymphnodes, spleen;MALT
Haematopoetic system
Macrophages – frontline of innate immune
defense
J Clin Invest. 2002;110(11):1603-1605. doi:10.1172/JCI17302
Macrophages
• Named by Elie Metchnikoff : „microorganims can be engulfed
and digested by phagocytic cells“
• Progenitor in the blood: monocytes
– Different in the lung: self renewal, proliferation
• Resident in tissue
– Alveoli  alveolar macrophages
– interstitium
• Relatively long-lived (ca. 40% in 1 year)
• Frontline/first line of antigen recognition and defense !
Macrophages - scavengers
© Dr Dennis Kunkel
• Professional phagocytes:
 engulf and kill invading pathogens (microorganism, particles)
 cell debris and infected cells
 distinguish between „dangerous“ and „harmless“ antigens
• Equipped with pattern recognition receptors and can rapidly produce
proinflammatory cytokines and chemokines
Bliska&Casadevall Nat. Reviews
Microbiology2009
Depletion of alveolar macrophages
impairs neutrophil emigration after LPS
impaired neutrophil evasion after alveolar macrophage depletion (open
bars) in response to intratracheal LPS stimulation
Maus et al., AJP Lung 2002
Recruitment of immune cells by macrophages
Monocytes
• 5-8 %
• many lysosomes
• Differentiate into lung DC and Macrophages
lung M
PBMo
lung DC
Recruitment of monocytes
Granulocytes/polymorphonuclear leukocytes
• Cytoplasmic granules
• Irregularly shaped nuclei
• Short lived
Neutrophils (PMN)
• The main effector of innate immunity (55-70%)
• Phagocytes
• Kills the pathogens mainly by ROS and enzymes (e.g., neutrophil
elastase)
• 2 types of vesicles:
1) lysosomal enzymes
2) collagenase and lactoferrin (toxic)
• Become apoptotic after some hours to days or after phagocytosis
of pathogen
Leukocyte emigration to the lung:
Adhesion molecules
Neutrophils-NETosis
• Release of granule proteins and chromatin  extracellular fibers
bind gram-pos. and –neg. bacteria
• NETs: neutrophil extracellular traps
 degradation of virulence factors, kill bacteria
Neutrophil
Extracellular Traps
Kill Bacteria ;
Brinkmann et al. Science 2004
immunopaedia.org
Neutrophils-NETosis
A) Inactive neutrophils
B) active neutrophils
E) extracellular NETs
Bacteria trapped in NETs
A) Staphylococcus aureus
B) Salmonella typhimurium
Young et al. PlosONE 2011
• 2-5% of leukocytes
• Granules: enzymes & toxic proteins
• Important for defense against parasites
• MBP: major basic protein
• Attack surfaces that are marked with IgE (cells
or parasites)
• Involved in allergic inflammatory reactions
• Also important role in attacking the mucosa
and the airway epithelium in asthma
www.laborlexikon.de
Eosinophils
Eosinophils – Asthma bronchiale
Bronchus
Knochenmark
Antigen
Mastzelle
Eosinophiler
Granulozyt
TH 2-Zelle
BronchialSchaden
Interleukin-4
GM-CSF
Interleukin-5
Histamin
Leukotriene
IL-4, IL-13
Granula-Proteine
Leukotriene
Verlängertes Überleben
IL-13
Chemokine
(RANTES, Eotaxin,
MCP-1, MIP-1α )
Selektin
VCAM-1
ICAM-1
Diapedese
Adhäsion
Endothelium
Blut
NEJM 344, 350-362, 2001
Basophils
• Less than 1% of Leukocytes
• Contain histamine and heparin
• Proteolytic enzymes
• Fast immune reaction; external antigens (asthma, hay fever)
Mast cells
• only in tissue and mucosa
• bind IgE on their surface
• degranulate among antigen contact and release histamin,
leukotrienes etc. from their granulas
• main cells which confer acute allergic symptoms (swelling,
bronchial obstruction) in acute asthma etc.
Mast cells - activation
Bischoff 2007
Asthma bronchiale
cross-linking of membrane-bound IgE by
allergenes
Activation
Release of:
histamine, leukotrienes, proteoglycans
cytokines (IL-1,2,3,4,5, TNF-α, GMCSF)
early response
bronchial spasm
oedema
bronchial obstruction
late response
mucosal inflammation
bronchial obstruction
bronchial hyperreactivity
development of matrix
Dendritic cells (DC)
• Myeloid and lymphoid progenitors (small subpopulation); lat. dendriticus =
branched (verzweigt)
• Key cells: link innate with adaptive immunity
• Immature DCs: phagocytic - enter tissue & mature after pathogen encountering
Lambrecht & Hammad, 2003
Dendritic cells
Main function: Antigen presenting cell (APC)
Lambrecht & Hammad, 2003
Dendritic cells
• Secondary immune response:
Lambrecht & Hammad, 2003
Dendritic cells
• Mature DCs shape t-cell response
(Hammad & Lambrecht, J Allergy Clin Immunol
2006) :
• Which type of t-cells is activated?
• Different Ils or different
concentrations
• Defines tolerance vs. Immunity
• Immature DCs cannot activate
naive T cells.
Dendritic Cells (DC)
pattern recognition
receptors
(TLR 2,4,7,9...)
integrins
(CD11b, CD11c)
MHC class II
maturation
antigen presentation
MHC class II 
co-stimulatory CD80/CD86 
phagocytosis capacity 
T cell stimulation 
antigen uptake
immature DC
mature DC
Antigen presentation via MHC-molecules
MHC= major histocompatibility complex; repertoire differs between individuals
MHC
Class II
MHC
Class I
CD8+
CD4+
Killing
Activation
Endogenous Antigens
MHC I: ubiquitous expr.
Exogenous Antigens
MHC II: professional APC
Antigen presenting cells
MHCII expression :
Constitutive on all professional APCs
costimulatory molecules
– present to CD4+ helper T-cells
– HLA-DR, DP, DQ
MHC I expresion:
Constitutive on all nucleated cells
– present to CD8+ cytotoxic T-cells
– HLA (Human Leukocyte
Antigen)A, B, C
Peptide loading of MHC molecules
Phagocytosis
Endocytic
pathway
Postranslational
modifications
Secretory
pathway
Cross presentation of soluble antigen on MHC class I
Mainly in dendritic cells => activation and recruitment of CD8+ T cells
Interaction of MHC- molecules with T-cell receptors
Small T-cell subpopulation: γδ-TCR => much less variable repertoire: 103 vs. 1015 (αβ)
Interaction of MHC- molecules with T-cell receptors
Signals required for activation:
1. Antigen-specific binding TCR-MHC
2. Co-stimulatory molecules (e.g. CD28 interaction with CD80/CD86 (B7)
or ICOS with ICOS-L)
3. Cytokines (IL-4, -15, -12 or TGF-ß)
Gutcher et al., JCI, 2007
Haematopoetic system
T lymphocytes
T lymphocytes
Helper T cell (Th-CD4+)
Activated helper T cell
– “The Bureaucrat”
– Directs other cells
– Uses cytokines as its “memos”
Cytotoxic T cell (Tc-CD8+)
Activated killer cell
– “The Hitman”
– Kills on contact
– Also produces cytokines (IFN-,
TNF-a)
T helper cells
T helper cells
T helper cell subtypes
Dysbalance between the subtypes => (chronic) imflammatory diseases
Février et al., Viruses, 2011
Cytotoxic T cells
Regulatory T cells
Regulatory T cells
Effector T cells
homeostasis
inflammation
inflammation
Image derived from Bouma & Strober et al., Nature Reviews Immunology,
Regulatory T cells
Mode of action
Valadi et al., Nature Reviews Immunology, 2008
B lymphocytes
Establishment of a first, antibody-mediated
immune response: ~ 7days
Secondary immune response: ~3 days
en.wikipedia.org
Antibodies
Antibody functions
austincc.edu
Antibody classes
Thank you for your attention!
„Es war einmal das Leben“, Albert Barillé, 1978-1995