Lymphoid architecture & Leukocyte recirculation Thursday Jan 26th, 2017
Topics The life of immune cells Where are they born? Where are they educated? Where do they function? How do they get there?
The main organs of the immune system Primary Lymphoid Tissues Secondary Lymphoid Tissues
The immune system HSC
ETP to Thymus https://stemcells.nih.gov/info/regenerative_medicine/2006chapter2.htm
Bone marrow anatomy Sinus Blood vessels Megakaryocytes HSC HSC niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone doi:10.1038/nature12984
doi:10.1038/nri1779 MPP = multipotent projenitor
B cell development CXCR4 doi:10.1038/nri3570
Early Thymic Precursors : Moving-in into the Thymus??? DOI: 10.5772/58699
The multi-step model of leukocyte homing Nature Reviews Immunology (2005) 5: 546
Leukocyte trafficking is mediated 3 families of molecules: Selectins: Lectins that bind to carbohydrate ligands with low affinity. Integrins: A large family of heterodimeric proteins that bind to a variety of cellular adhesion molecules and extracellular matrix components. Chemoattractant receptors: G-protein coupled receptors that can trigger upregulation of integrin affinity and avidity by inducing rapid and reversible conformation changes and integrin clustering, and induce chemotaxis along a ligand gradient.
doi:10.1038/nri2156 Integrin activation during chemotactic receptor outside-in signaling
Structural basis of LFA-1 activation Courtesy of Tim Springer
doi:10.1038/nri2156 Getting to the other side
Homing to the thymus doi: 10.1073/pnas.0602024103
Thymus & T cell Development http://lecannabiculteur.free.fr/sites/univ%20w.australia/mb140/corepages/lymphoid1/lymph1.htm doi: 10.1002/eji.201445277
CXCR4 CCR9 CCR7??? -additional factors ~2 weeks doi:10.1038/ni1323
sphingosine-1-phosphate (S1P) doi:10.1038/nri2400 S1P - bioactive sphingolipid metabolite: cell growth, survival, differentiation, lymphocyte trafficking, vascular integrity and cytokine and chemokine production Generated by erythrocytes
sphingosine-1-phosphate (S1P) S1P - bioactive sphingolipid metabolite: cell growth, survival, differentiation, lymphocyte trafficking, vascular integrity and cytokine and chemokine production doi:10.1038/nri2974
Mature lymphocytes have access to the whole body
Lymph vessels: tissue fluid homeostasis (Choi, Cold Spring Harb Perspect Med, 2012)
Secondary Lymphoid Organs 500-600 LN / adult
Why do T and B cells recirculate? T cell repertoire and antigen detection DOI: 10.1016/j.immuni.2014.07.007
doi:10.1038/nri3442
Architecture of secondary lymphoid tissues Lymph Node (Girard, Nature Reviews Imm, 2012) (exit)
Lymphatics B Cells T Cells Stroma HEV DC
C e 3D Visualization of Whole 3D Organs CD31 B220 CD8 CD169 Lyve1 unpublished - With Weizhe Li
Red pulp: hematopoiesis, blood filtration (damaged platelets, old erythrocytes, dead cells, iron recycling White pulp and marginal zone transit area: Highly organized lymphoid compartment
Architecture of secondary lymphoid tissues Spleen doi:10.1038/nri2588
Architecture of secondary lymphoid tissues Peyer s Patches No afferent lymphatics specialized M cells directly sample the lumen!
RAG2-GFP Lymphocyte motility in LNs ~6-10um/min
RAG2-GFP Lymphocyte motility in LNs ~6-10um/min
doi:10.1038/nri2588 CONDUITS and STROMA in cell migration
FRCs also act as immune modulators: They make IL-7 that supports T cell survival: They can directly modulate T cell responses:
What happens during an immune response doi:10.1038/ni.1822
Retention of activated T cells in lymphoid tissues doi:10.1038/nri2974
DC mediated CD4+ T cell activation 6 Hours PI CD8 + T cells (OT-I) CD4 + T cells (OT-II) Particulate Antigen DC (CD11c)
Phases of T cell motility during priming doi: 10.3389/fimmu.2015.00559
Effector T cells express distinct chemokine receptors doi:10.1038/ni.f.213
Tfh / B cell interactions CXCR4 CXCR5 CCR7 doi:10.1038/nri3802
doi:10.1038/nri3755 EBI2 chemotactic axis in B cell migration
Retention of activated T cells in lymphoid tissues doi:10.1038/nri2974
T cell recirculation Klaus Ley and Geoffrey S. Kansas, Nature Reviews Immunology 2004
Location dictates homing and differentiation doi:10.1038/nri3442
T cell recirculation Klaus Ley and Geoffrey S. Kansas, Nature Reviews Immunology 2004
Without activation, vascular endothelial cells do not support leukocyte recruitment
Infection or tissue damage activates endothelial cells, upregulating adhesion molecules/chemokines facilitating cell recruitment P-selectin CXCL1/2 VCAM-1 IL-1 TNF-a Adaptive Response : earliest day 3
Innate Immune System - the 1 st Response doi: https://doi.org/10.1182/blood-2009-06-221630
doi: 10.1038/nature12175 The Neutrophil Swarm
doi: 10.1038/nature12175 The Neutrophil Swarm
doi:10.1038/nri.2016.49 Neutrophils - the 1 st Response
doi:10.1038/nri3671 Monocytes come in
Emergency hematopoiesis: feedback to the origin doi:10.1038/nri3660
T cells migrating back into the tissue undergo a similar process: DOI: http://dx.doi.org/10.1016/j.it.2015.07.002
Memory T cell recirculation patterns: T RM are special http://dx.doi.org.offcampus.lib.washington.edu/10.1016/j.coviro.2016.11.011
doi:10.1038/nri.2015.3
doi:10.1038/nri1886 All the way back to the bone marrow
Questions.