Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses

Nadafi, Reza; Graça, Catarina; Keuning, Eelco D.; Koning, Jos J. de; Kivit, Sander de; Konijn, Tanja; Henri, Sandrine; Borst, Jannie; Reijmers, Rogier M.; Baarsen, Lisa G. M. van; Mebius, Reina E.

doi:10.1016/j.celrep.2020.03.007

Cited by 51 publications

(66 citation statements)

References 71 publications

(98 reference statements)

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“…However, RA is an important risk factor [51] for this type of diabetes, possibly due to RA-driven inflammation [52]. Since it has been shown that murine LNSCs can control the formation of autoreactive T cells by presenting specific PTA in the context of MHC molecules [27,32,53], it is possible to speculate that LNSCs obtained from RA patients are not capable of suppressing RRAD-specific T cells due to lower expression of this PTA. Although the limitation of our study is the low number of PTAs we analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, expression and subsequent presentation of PTAs by LNSC in the context of MHC class II to CD4+ T cells can also lead to maintenance of T regs [31]. Moreover, recently we demonstrated that LNSCs convert naïve autoreactive CD4+ T cells into antigen-specific T regs cells and suppress autoreactive T follicular helper (T fh ) and B cells responses [32].…”

Section: Introductionmentioning

confidence: 99%

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

Hähnlein

Nadafi

Jong

et al. 2020

IJMS

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hähnlein

Nadafi

Jong

et al. 2020

IJMS

Self Cite

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“…Recently, a novel organoid composed of cells derived from lymph node and tumor tissue from the same patient was developed to evaluate the efficacy of immunotherapy and to assess the relationship between the clinical response of the patient to therapy ( 163 ). Lymph node stromal cells (LNSCs) have been reported to be involved in the inhibition of early activation of autoreactive immune cells and peripheral tolerance ( 164 ). Mechanisms can be clarified using this advanced organoid model.…”

Section: Challenges and Future Developmentsmentioning

confidence: 99%

Immunotherapy for Ovarian Cancer: Adjuvant, Combination, and Neoadjuvant

et al. 2020

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Ovarian cancer is the most lethal gynecologic malignancy. Surgery and chemotherapy are the primary treatments for ovarian cancer; however, patients often succumb to recurrence with chemotherapeutic resistance within several years after the initial treatment. In the past two decades, immunotherapy has rapidly developed, and has revolutionized the treatment of various types of cancer. Despite the fact that immunotherapy response rates among ovarian cancer patients remain modest, treatment with immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR)- and TCR-engineered T cells is rapidly developing. Therapeutic efficiency could be improved significantly if immunotherapy is included as an adjuvant therapy, in combination with chemotherapy, radiation therapy, and the use of anti-angiogenesis drugs, and poly ADP ribose polymerase inhibitors (PARPi). Newly developed technologies that identify therapeutic targets, predict treatment efficacy, rapidly screen potential immunotherapy drugs, provide neoadjuvant immunotherapy, and utilize nanomedicine technology provide new opportunities for the treatment of ovarian cancer, and have the potential to prolong patient survival. However, important issues that may hinder the efficacy of such approaches, including hyperprogressive disease (HPD), immunotherapy-resistance, and toxicity of the treatments, including neurotoxicity, must be taken into account and addressed for these therapies to be effective.

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“…Murine LNSCs can additionally acquire from DCs peptide–MHCII complexes that they present to CD4 + T cell in order to promote their dysfunction ( Figure 2 A) [ 51 ]. MHCII expression by LECs and FRCs has been shown to play important roles in Treg homeostasis in mice ( Figure 2 A) [ 52 , 53 ]. Our laboratory recently demonstrated that abolition of genetic MHCII expression in murine LNSCs, especially in LECs, impacts Treg proliferation in LNs and leads to the development of spontaneous features of autoimmunity in elderly mice [ 54 ].…”

Section: Lnscs Function As a Brake For The Development Of T Cell-mmentioning

confidence: 99%

Lymph Node Stromal Cells: Mapmakers of T Cell Immunity

Harlé

Kowalski

Garnier

et al. 2020

IJMS

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Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell maturation, migration and activation. Recent characterizations of SCs have expanded our understanding of their heterogeneity and suggested a functional specialization of distinct SC subsets, further modulated by the microenvironment. Lymph node SCs (LNSCs) have been shown to be particularly important in maintaining immune homeostasis and T cell tolerance. Under inflammation situations, such as viral infections or tumor development, SCs undergo profound changes in their numbers and phenotype and play important roles in contributing to either the activation or the control of T cell immunity. In this review, we highlight the role of SCs located in LNs in shaping peripheral T cell responses in different immune contexts, such as autoimmunity, viral and cancer immunity.

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Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses

Abstract: Highlights d Lymph node stromal cells convert naive CD4 + T cells into T REG cells d Conversion of T REG cells by lymph node stromal cells is IL-2 dependent d Autoreactive T FH cells and B cells are controlled by lymph node stromal cells

Cited by 51 publications

References 71 publications

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

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

Immunotherapy for Ovarian Cancer: Adjuvant, Combination, and Neoadjuvant

Lymph Node Stromal Cells: Mapmakers of T Cell Immunity

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