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Immune cells in the lung
Nunja C. Habel-Ungewitter & Sabine Bartel12.11.14
immunity
• from immunis, Latin for "exempt“• capability of the body to resist harmful
microbes from entering it• Immunity involves both specific and non-
specific components
immunity
Innate vs. adaptive immunity
Adaptive immune response
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
Innate and adaptive immunity
The immune system: overview
Antibody productionOpsonization
Antigen presentation
Complement system
Complement system
"Janeway's Immunobiology"
Primary lymphatic organs: generation of lymphocytes
bone marrow, thymus
Secondary lymphatic organs: initiation of adaptive immune responses
lymphnodes, spleen;MALT
Tonsils and adenoids
Lymph nodes
Bone marrow
Appendix
Lymphatic vessels
Lymph nodes
Thymus
Peyer’s patches
Spleen
Lymphatic vessels
Lymph nodes
Lymphatic organs
Haematopoetic system
Macrophages – frontline of innate immune defense
J Clin Invest. 2002;110(11):1603-1605. doi:10.1172/JCI17302
• 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
Macrophages - scavengers• 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
© D
r D
enni
s K
unke
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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
lung DC
PBMo
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 enzymes2) 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 fibersbind 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
Young et al. PlosONE 2011
A) Inactive neutrophils B) active neutrophils E) extracellular NETs
Bacteria trapped in NETsA) Staphylococcus aureus B) Salmonella typhimurium
Eosinophils
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• 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
Eosinophils – Asthma bronchialeBronchus
Antigen
Knochenmark
EosinophilerGranulozyt
TH 2-Zelle
Bronchial-Schaden
Granula-ProteineLeukotriene
IL-13
Verlängertes Überleben
Interleukin-4GM-CSFInterleukin-5
Selektin
VCAM-1ICAM-1
Adhäsion
Endothelium
Blut
Diapedese
Chemokine(RANTES, Eotaxin,
MCP-1, MIP-1α )
HistaminLeukotrieneIL-4, IL-13
Mastzelle
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)
Lambrecht & Hammad, 2003
• 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
Dendritic cells
Lambrecht & Hammad, 2003
Main function: Antigen presenting cell (APC)
Dendritic cells• Secondary immune response:
Lambrecht & Hammad, 2003
• 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
Dendritic Cells (DC)
integrins(CD11b, CD11c)
pattern recognition receptors
(TLR 2,4,7,9...)
antigen uptake
immature DC
maturation
antigen presentationMHC class II
co-stimulatory CD80/CD86 phagocytosis capacity
T cell stimulation
mature DC
MHC class II
MHC Class I
MHC Class II
CD4+ CD8+
Endogenous Antigens Exogenous Antigens
MHC I: ubiquitous expr. MHC II: professional APC
MHC= major histocompatibility complex; repertoire differs between individuals
Killing Activation
Antigen presentation via MHC-molecules
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
Postranslational modifications
Secretory pathway
Endocytic pathway
Phagocytosis
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
Helper T cell (Th-CD4+) Cytotoxic T cell (Tc-CD8+)
Activated helper T cell– “The Bureaucrat”– Directs other cells– Uses cytokines as its “memos”
Activated killer cell– “The Hitman”– Kills on contact– Also produces cytokines (IFN-,
TNF-
T lymphocytes
T helper cells
T helper cells
T helper cell subtypes
Février et al., Viruses, 2011
Dysbalance between the subtypes => (chronic) imflammatory diseases
Cytotoxic T cells
Regulatory T cells
Regulatory T cellsEffector T cells
homeostasis
inflammation inflammation
Image derived from Bouma & Strober et al., Nature Reviews Immunology,
Mode of action
Regulatory T cells
Valadi et al., Nature Reviews Immunology, 2008
en.wikipedia.org
B lymphocytes
Establishment of a first, antibody-mediated immune response: ~ 7daysSecondary immune response: ~3 days
Antibodies
Antibody functions
austincc.edu
Antibody classes
Thank you for your attention!
„Es war einmal das Leben“, Albert Barillé, 1978-1995
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