Lymphoid architecture & Leukocyte recirculation. Thursday Jan 26th, 2017

Transcription

1 Lymphoid architecture & Leukocyte recirculation Thursday Jan 26th, 2017

2 Topics The life of immune cells Where are they born? Where are they educated? Where do they function? How do they get there?

3 The main organs of the immune system Primary Lymphoid Tissues Secondary Lymphoid Tissues

4 The immune system HSC

5 ETP to Thymus

6 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: /nature12984

7 doi: /nri1779 MPP = multipotent projenitor

8 B cell development CXCR4 doi: /nri3570

9 Early Thymic Precursors : Moving-in into the Thymus??? DOI: /58699

10 The multi-step model of leukocyte homing Nature Reviews Immunology (2005) 5: 546

11 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.

12 doi: /nri2156 Integrin activation during chemotactic receptor outside-in signaling

13 Structural basis of LFA-1 activation Courtesy of Tim Springer

14 doi: /nri2156 Getting to the other side

15 Homing to the thymus doi: /pnas

16 Thymus & T cell Development doi: /eji

17 CXCR4 CCR9 CCR7??? -additional factors ~2 weeks doi: /ni1323

18 sphingosine-1-phosphate (S1P) doi: /nri2400 S1P - bioactive sphingolipid metabolite: cell growth, survival, differentiation, lymphocyte trafficking, vascular integrity and cytokine and chemokine production Generated by erythrocytes

19 sphingosine-1-phosphate (S1P) S1P - bioactive sphingolipid metabolite: cell growth, survival, differentiation, lymphocyte trafficking, vascular integrity and cytokine and chemokine production doi: /nri2974

20 Mature lymphocytes have access to the whole body

21 Lymph vessels: tissue fluid homeostasis (Choi, Cold Spring Harb Perspect Med, 2012)

22 Secondary Lymphoid Organs LN / adult

23 Why do T and B cells recirculate? T cell repertoire and antigen detection DOI: /j.immuni

24 doi: /nri3442

25 Architecture of secondary lymphoid tissues Lymph Node (Girard, Nature Reviews Imm, 2012) (exit)

26 Lymphatics B Cells T Cells Stroma HEV DC

27 C e 3D Visualization of Whole 3D Organs CD31 B220 CD8 CD169 Lyve1 unpublished - With Weizhe Li

28 Red pulp: hematopoiesis, blood filtration (damaged platelets, old erythrocytes, dead cells, iron recycling White pulp and marginal zone transit area: Highly organized lymphoid compartment

29 Architecture of secondary lymphoid tissues Spleen doi: /nri2588

30 Architecture of secondary lymphoid tissues Peyer s Patches No afferent lymphatics specialized M cells directly sample the lumen!

31 RAG2-GFP Lymphocyte motility in LNs ~6-10um/min

32 RAG2-GFP Lymphocyte motility in LNs ~6-10um/min

33 doi: /nri2588 CONDUITS and STROMA in cell migration

34 FRCs also act as immune modulators: They make IL-7 that supports T cell survival: They can directly modulate T cell responses:

35 What happens during an immune response doi: /ni.1822

36 Retention of activated T cells in lymphoid tissues doi: /nri2974

37 DC mediated CD4+ T cell activation 6 Hours PI CD8 + T cells (OT-I) CD4 + T cells (OT-II) Particulate Antigen DC (CD11c)

38 Phases of T cell motility during priming doi: /fimmu

39 Effector T cells express distinct chemokine receptors doi: /ni.f.213

40 Tfh / B cell interactions CXCR4 CXCR5 CCR7 doi: /nri3802

41 doi: /nri3755 EBI2 chemotactic axis in B cell migration

42 Retention of activated T cells in lymphoid tissues doi: /nri2974

43 T cell recirculation Klaus Ley and Geoffrey S. Kansas, Nature Reviews Immunology 2004

44 Location dictates homing and differentiation doi: /nri3442

45 T cell recirculation Klaus Ley and Geoffrey S. Kansas, Nature Reviews Immunology 2004

46 Without activation, vascular endothelial cells do not support leukocyte recruitment

47 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

48 Innate Immune System - the 1 st Response doi:

49 doi: /nature12175 The Neutrophil Swarm

50 doi: /nature12175 The Neutrophil Swarm

51 doi: /nri Neutrophils - the 1 st Response

52 doi: /nri3671 Monocytes come in

53 Emergency hematopoiesis: feedback to the origin doi: /nri3660

54 T cells migrating back into the tissue undergo a similar process: DOI:

55

56 Memory T cell recirculation patterns: T RM are special

57 doi: /nri

58 doi: /nri1886 All the way back to the bone marrow

59 Questions.