Faculty Opinions recommendation of Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation.

Non-hematopoietic lymph node stromal cells shape immunity by inducing MHC-I-dependent deletion of self-reactive CD8+ T cells and MHC-II-dependent anergy of CD4+ T cells. In this study, we show that MHC-II expression on lymph node stromal cells is additionally required for homeostatic maintenance of regulatory T cells (Tregs) and maintenance of immune quiescence. In the absence of MHC-II expression in lymph node transplants, i.e. on lymph node stromal cells, CD4+ as well as CD8+ T cells became activated, ultimately resulting in transplant rejection. MHC-II self-antigen presentation by lymph node stromal cells allowed the non-proliferative maintenance of antigen-specific Tregs and constrained antigen-specific immunity. Altogether, our results reveal a novel mechanism by which lymph node stromal cells regulate peripheral immunity.

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Human Lymph Node Stromal Cells Have the Machinery to Regulate Peripheral Tolerance during Health and Rheumatoid Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms21165713 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5713

Author(s):

Janine S. Hähnlein ◽

Reza Nadafi ◽

Tineke A. de Jong ◽

Johanna F. Semmelink ◽

Ester B. M. Remmerswaal ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Lymph Node ◽

Antigen Presentation ◽

Stromal Cells ◽

Immune Modulation ◽

Ex Vivo ◽

Human Leukocyte ◽

Interferon Γ ◽

Peripheral Tolerance ◽

Lymph Node Stromal Cells

Background: In rheumatoid arthritis (RA) the cause for loss of tolerance and anti-citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that lymph node stromal cells (LNSCs) maintain peripheral tolerance through presentation of peripheral tissue antigens (PTAs). We hypothesize that dysregulation of peripheral tolerance mechanisms in human LNSCs might underlie pathogenesis of RA. Method: Lymph node (LN) needle biopsies were obtained from 24 RA patients, 23 individuals positive for RA-associated autoantibodies but without clinical disease (RA-risk individuals), and 14 seronegative healthy individuals. Ex vivo human LNs from non-RA individuals were used to directly analyze stromal cells. Molecules involved in antigen presentation and immune modulation were measured in LNSCs upon interferon γ (IFNγ) stimulation (n = 15). Results: Citrullinated targets of ACPAs were detected in human LN tissue and in cultured LNSCs. Human LNSCs express several PTAs, transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor 1 (DEAF1), and molecules involved in citrullination, antigen presentation, and immunomodulation. Overall, no clear differences between donor groups were observed with exception of a slightly lower induction of human leukocyte antigen-DR (HLA-DR) and programmed cell death 1 ligand (PD-L1) molecules in LNSCs from RA patients. Conclusion: Human LNSCs have the machinery to regulate peripheral tolerance making them an attractive target to exploit in tolerance induction and maintenance.

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Modes of Antigen Presentation by Lymph Node Stromal Cells and Their Immunological Implications

Frontiers in Immunology ◽

10.3389/fimmu.2015.00446 ◽

2015 ◽

Vol 6 ◽

Cited By ~ 24

Author(s):

Sachiko Hirosue ◽

Juan Dubrot

Keyword(s):

Lymph Node ◽

Antigen Presentation ◽

Stromal Cells ◽

Lymph Node Stromal Cells

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Absence of MHC-II expression by lymph node stromal cells results in autoimmunity

Life Science Alliance ◽

10.26508/lsa.201800164 ◽

2018 ◽

Vol 1 (6) ◽

pp. e201800164 ◽

Cited By ~ 7

Author(s):

Juan Dubrot ◽

Fernanda V Duraes ◽

Guillaume Harlé ◽

Anjalie Schlaeppi ◽

Dale Brighouse ◽

...

Keyword(s):

Endothelial Cells ◽

Lymph Node ◽

T Cell ◽

Mhc Class Ii ◽

Stromal Cells ◽

Inducible Promoter ◽

Autoantibody Production ◽

T Cell Infiltration ◽

Ifn Γ ◽

Lymph Node Stromal Cells

How lymph node stromal cells (LNSCs) shape peripheral T-cell responses remains unclear. We have previously demonstrated that murine LNSCs, lymphatic endothelial cells (LECs), blood endothelial cells (BECs), and fibroblastic reticular cells (FRCs) use the IFN-γ–inducible promoter IV (pIV) of the MHC class II (MHCII) transactivator CIITA to express MHCII. Here, we show that aging mice (>1 yr old) in which MHCII is abrogated in LNSCs by the selective deletion of pIV exhibit a significant T-cell dysregulation in LNs, including defective Treg and increased effector CD4+ and CD8+ T-cell frequencies, resulting in enhanced peripheral organ T-cell infiltration and autoantibody production. The proliferation of LN-Tregs interacting with LECs increases following MHCII up-regulation by LECs upon aging or after exposure to IFN-γ, this effect being abolished in mice in which LECs lack MHCII. Overall, our work underpins the importance of LNSCs, particularly LECs, in supporting Tregs and T-cell tolerance.

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Neonatal lymph node stromal cells drive myelodendritic lineage cells into a distinct population of CX3CR1+CD11b+F4/80+ regulatory macrophages in mice

Blood ◽

10.1182/blood-2011-06-359315 ◽

2012 ◽

Vol 119 (17) ◽

pp. 3975-3986 ◽

Cited By ~ 7

Author(s):

Xiangyue Zhang ◽

Songfeng Yu ◽

Katharina Hoffmann ◽

Kai Yu ◽

Reinhold Förster

Keyword(s):

Dendritic Cells ◽

Lymph Node ◽

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Stromal Cells ◽

Cell Activation ◽

Distinct Population ◽

Lymph Node Stromal Cells

Abstract Beyond providing a scaffold for immune cells, recent studies indicate that lymph node stromal cells provide potent regulatory capacities that affect the quality of adaptive immune responses. In this study, we provide evidence that neonatal lymph node stromal cells (nnLNSCs) consistently promote the differentiation of macrophage dendritic cell progenitors as well as mature and immature dendritic cells into a distinct population of CX3CR1+ CD11b+F4/80+ regulatory macrophages (regMΦ). These cells possess remarkably low levels of T cell costimulatory molecules as well as MHC class II molecules. regMΦ do not interfere with early T-cell activation but, via nitric oxide secretion, efficiently suppress T-cell proliferation. Furthermore, CD4+ T cells proliferating in the presence of regMΦ gain immunosuppressive capacity and MΦ isolated from day 3 nnLNs are T-cell immunosuppressive. Adoptive transfer of antigen-loaded regMΦ induce a profound antigen-specific immune suppression in vivo. Together our data show that nnLNSCs skew the differentiation of dendritic cells and their progenitors toward regMΦ, thus revealing a novel mechanism for local immune regulation.

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