Fibroblastic Reticular Cells in Secondary Lymphoid Organs

Mechthild Lütge

Institute of Immunobiology

Kantonsspital St.Gallen, Switzerland

Lymph Nodes

Spleen

Peyer's patches

Secondary Lymphoid organs (SLO)

Dedicated sites where adaptive immunity is mounted to pathogens in the lymph, blood or intestine

Fibroblastic reticular cells orchestrate SLO organization

Acton et al. Trends in Immunology, 2021

Fibroblastic reticular cells orchestrate SLO organization

Acton et al. Trends in Immunology, 2021

Fibroblastic reticular cells orchestrate SLO organization

Fibroblastic reticular cells (FRC):

• provide structural foundation
• guide cellular interactions
• provide signals for immune cell survival, activation and differentiation

Acton et al. Trends in Immunology, 2021

Fibroblastic reticular cells orchestrate SLO organization

Fibroblastic reticular cells (FRC):

• provide structural foundation
• guide cellular interactions
• provide signals for immune cell survival, activation and differentiation

→ Decision making process (strength and specificity of immune response)

Acton et al. Trends in Immunology, 2021

Fibroblastic reticular cells orchestrate SLO organization

To what extend are FRC underpinned niches functionally conserved across:

Fibroblastic reticular cells orchestrate SLO organization

To what extend are FRC underpinned niches functionally conserved across:

(1.)  SLOs?

Fibroblastic reticular cells orchestrate SLO organization

To what extend are FRC underpinned niches functionally conserved across:

(1.)  SLOs?

(2.) Species?

Fibroblastic reticular cells orchestrate SLO organization

To what extend are FRC underpinned niches functionally conserved across:

(1.)  SLOs?

(2.) Species?

→ What factors shape FRC subset identity and function?

Fibroblastic reticular cells orchestrate SLO organization

• Conserved stromal–immune cell circuits secure B cell homeostasis and function

B cell zone reticular cells direct efficient humoral immunity

CXCL13  CCL19/CCL21

CXCL13+ FRC = B cell zone reticular cells (BRCs)

B cell zone reticular cells direct efficient humoral immunity

CXCL13  CCL19/CCL21

CXCL13+ FRC = B cell zone reticular cells (BRCs)

B cell zone reticular cells direct efficient humoral immunity

• to what extend are BRC underpinned niches functionally conserved across SLO?

CXCL13  CCL19/CCL21

CXCL13+ FRC = B cell zone reticular cells (BRCs)

B cell zone reticular cells direct efficient humoral immunity

• to what extend are BRC underpinned niches functionally conserved across SLO?

• Systemic humoral immunity?

CXCL13  CCL19/CCL21

CXCL13+ FRC = B cell zone reticular cells (BRCs)

B cell zone reticular cells direct efficient humoral immunity

• to what extend are BRC underpinned niches functionally conserved across SLO?

• Systemic humoral immunity?

• What are major pathways controlling BRC-immune cell interactions?

CXCL13  CCL19/CCL21

CXCL13+ FRC = B cell zone reticular cells (BRCs)

B cell zone reticular cells direct efficient humoral immunity

• to what extend are BRC underpinned niches functionally conserved across SLO?

• Systemic humoral immunity?

• What are major pathways controlling BRC-immune cell interactions?

• Are these interactions functionally redundant across SLOs?

CXCL13  CCL19/CCL21

CXCL13+ FRC = B cell zone reticular cells (BRCs)

Shared B cell follicle and PI16+ BRC subset identity across SLOs

Onder L et al., Immunity, 2017

Lütge et al. Nat. Immunol., 2023

Shared B cell follicle and PI16+ BRC subset identity across SLOs

Onder L et al., Immunity, 2017

Lütge et al. Nat. Immunol., 2023

Shared B cell follicle and PI16+ BRC subset identity across SLOs

Onder L et al., Immunity, 2017

Lütge et al. Nat. Immunol., 2023

Developmental and anatomical gene sets imprint BRC identity

Lütge et al. Nat. Immunol., 2023

Developmental and anatomical gene sets imprint BRC identity

Lütge et al. Nat. Immunol., 2023

Developmental and anatomical gene sets imprint BRC identity

Lütge et al. Nat. Immunol., 2023

Subset identity

Developmental and anatomical gene sets imprint BRC identity

Lütge et al. Nat. Immunol., 2023

→ Organ-specific gene sets reflect developmental and anatomical imprints

Subset identity

Niche factors and signaling pathways define subset identity and function

Lütge et al. Nat. Immunol., 2023

Subset-specific niche factors

Subset-specific signaling pathways

Niche factors and signaling pathways define subset identity and function

Lütge et al. Nat. Immunol., 2023

→ Subset-specific gene sets that are consistently found across SLOs point to BRC modulation by immune cells

Subset-specific niche factors

Subset-specific signaling pathways

Conserved feedforward BRC-immune cell circuits sustain functional BRC niches

Lütge et al. Nat. Immunol., 2023

→ BRC-derived niche factors determine immune cell function

Conserved feedforward BRC-immune cell circuits sustain functional BRC niches

Lütge et al. Nat. Immunol., 2023

→ BRC-derived niche factors determine immune cell function

→ Leukocyte-derived maturation factors specify BRC subset identity

→ Conserved in humans

Conserved feedforward BRC-immune cell circuits sustain functional BRC niches

Lütge et al. Nat. Immunol., 2023

→ BRC-derived niche factors determine immune cell function

→ Leukocyte-derived maturation factors specify BRC subset identity

→ Conserved in humans

→ Validation?

Immune cell-derived maturation cues drive BRC differentiation and activation

Lütge et al. Nat. Immunol., 2023

In-vitro stimulation of CD45-CD31-EYFP+ cells:

→ PGRN, TGFb, IL-4 and VEGF-B drive BRC differentiation

Immune cell-derived maturation cues drive BRC differentiation and activation

Lütge et al. Nat. Immunol., 2023

In-vivo stimulation of lymph node FRC:

→ IL-1b drives FDC subset specification

Immune cell-derived maturation cues drive BRC differentiation and activation

Lütge et al. Nat. Immunol., 2023

FDC

B cell

PI16+RC

Mph/DC

T cell

Immune cell-derived maturation cues drive BRC differentiation and activation

Lütge et al. Nat. Immunol., 2023

FDC

B cell

PI16+RC

Mph/DC

T cell

CR2

ICAM1

IL6

Summary - 1: Advanced understanding of systemic humoral immunity

Lütge et al. Nat. Immunol., 2023

Lymph node

Spleen

Peyer's patch

Organ-specific imprints

Summary - 1: Advanced understanding of systemic humoral immunity

Lütge et al. Nat. Immunol., 2023

Lymph node

Spleen

Peyer's patch

Organ-specific imprints

Functional convergence

Summary - 1: Advanced understanding of systemic humoral immunity

Lütge et al. Nat. Immunol., 2023

Lymph node

Spleen

Peyer's patch

Organ-specific imprints

Functional convergence

Feedforward paradigm: circulating immune cell imprint B cell follicle niches in an organ indiscriminate manner thereby securing efficient systemic humoral immunity

Fibroblastic reticular cells orchestrate SLO organization

To what extend are FRC underpinned niches functionally conserved across:

(1.)  SLOs?

(2.) Species?

→ What factors shape FRC subset identity and function?

Fibroblastic reticular cells orchestrate SLO organization

To what extend are FRC underpinned niches functionally conserved across:

(1.)  SLOs?

(2.) Species?

→ What factors shape FRC subset identity and function?

Fibroblastic reticular cells orchestrate SLO organization

• PI16+ reticular cells support inflammation-induced remodeling in human lymph nodes

Repeated lymph node expansion and contraction throughout life

• Rapid expansion allows massive lymphocyte entry and proliferation

• Structural and functional tissue integrity is preserved

• FRC stretching and proliferation regulate network tension

Assen et al. Nat. Immunol., 2022

Repeated lymph node expansion and contraction throughout life

• Rapid expansion allows massive lymphocyte entry and proliferation

• Structural and functional tissue integrity is preserved

• FRC stretching and proliferation regulate network tension

Assen et al. Nat. Immunol., 2022

→ How does repeated expansion and contraction in response to immunological stimuli shape the FRC network in human lymph nodes?

The FRC landscape in human palatine tonsils

• No marginal zone reticular cells (MRCs) in palatine tonsils; antigen sampling occurs in the “reticulated” epithelium

De Martin et al. Nat. Immunol., 2023

The FRC landscape in human palatine tonsils

• No marginal zone reticular cells (MRCs) in palatine tonsils; antigen sampling occurs in the “reticulated” epithelium

• Subepithelial PI16+ reticular cells form a distinct niche show the strongest inflammation induced remodeling

• PI16+ reticular cells integrate immune cell-derived signals and govern T cell activation

De Martin et al. Nat. Immunol., 2023

The FRC landscape in human palatine tonsils

• No marginal zone reticular cells (MRCs) in palatine tonsils; antigen sampling occurs in the “reticulated” epithelium

• Subepithelial PI16+ reticular cells form a distinct niche show the strongest inflammation induced remodeling

• PI16+ reticular cells integrate immune cell-derived signals and govern T cell activation

De Martin et al. Nat. Immunol., 2023

→ Are there PI16+ reticular cells in human lymph nodes? Location? Response to inflammation?

Patient cohort –  clinically non-inflamed ("resting") cervical lymph nodes

Baseline immunoanatomy of "resting" human lymph nodes

• Extensive vasculature with a large perivascular space

• PDPN high B cell follicles/ PDPN low T cell zone

• B cell follicle are positioned throughout the LN

Baseline immunoanatomy of "resting" human lymph nodes

Baseline immunoanatomy of "resting" human lymph nodes

• Extensive vasculature with a large perivascular space

• PDPN high B cell follicles/ PDPN low T cell zone

• B cell follicle are positioned throughout the LN

Transcriptome analysis - Patient characteristics

Distinct FRC subsets form the perivascular niche in human lymph nodes

• Strong overlap with FRC landscape in human tonsils

• Distinct perivascular FRC subsets

• PI16+ reticular cells

    → Localization?

Transcriptome analysis - Patient characteristics

PI16+ RCs support inflammation-induced remodeling in human lymph nodes

• All FRC subset are conserved upon chronic activation

PI16+ RCs support inflammation-induced remodeling in human lymph nodes

Summary II: Fibroblastic reticular cells in human lymph nodes

Stereotypic «resting» human lymph node:

• extensive vasculature with a large perivascular space formed by distinct FRC subsets
• large number of B cell follicles positioned throughout the lymph node

Summary II: Fibroblastic reticular cells in human lymph nodes

Stereotypic «resting» human lymph node:

• extensive vasculature with a large perivascular space formed by distinct FRC subsets
• large number of B cell follicles positioned throughout the lymph node

PI16+ reticular cells:

• PI16+ RCs are located in the interfollicular and medullary region
• PI16+ RCs support inflammation-induced remodeling in human lymph nodes

Burkhard Ludewig Group

Angelina De Martin

Yves Stanossek

Lisa Kurz

Samuel Meili

Nadine Cadosch

Christian Perez-Shibayama

Cristina Gil-Cruz

Hung-Wei Cheng

Lucas Onder
 

Acknowledgements

Natalia Pikor Group

Sarah Grabherr

Department of

Otorhinolarnygology

Sandro Stöckli

University of Pennsylvania

Ivan Maillard

Joshua Brandstadter

University of Zurich

Mark Robinson

Charlotte Soneson