Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling

Brown, Flavian D.; Sen, Debattama R.; LaFleur, Martin W.; Godec, Jernej; Lukacs‐Kornek, Veronika; Schildberg, Frank A.; Kim, Hye-Jung; Yates, Kathleen B.; Ricoult, Stéphane J. H.; Bi, Kevin; Trombley, Justin D.; Kapoor, Varun; Stanley, Illana A.; Cremasco, Viviana; Danial, Nika N.; Manning, Brendan D.; Sharpe, Arlene H.; Haining, W. Nicholas; Turley, Shannon J.

doi:10.1038/s41590-019-0515-x

Cited by 63 publications

(87 citation statements)

References 65 publications

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“…In addition to nitric oxide production, sustained expression of MHCII by FRCs can mediate contraction of antigen-specific CD4 + T cells after peak expansion to limit prolonged inflammation caused by viral infection 116 . In contrast to mechanisms of restraint, FRCs can also enhance T cell fitness 117 . FRC-derived IL-6 leads to chromatin remodeling in CD8 + T cells to enhance their survival, metabolism and capacity to form tissueresident memory populations (Fig.…”

Section: Box 1 | Tertiary Lymphoid Structures (Tls) and Tls In Diseasementioning

confidence: 99%

Lymph node stromal cells: cartographers of the immune system

Krishnamurty¹,

Turley²

2020

Nat Immunol

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econdary lymphoid organs (SLOs), including lymph nodes (LNs), spleen and Peyer's patches (PPs), serve as the body's sites of immune cell surveillance. SLOs provide the infrastructure to maintain immune homeostasis and facilitate rapid and effective immune responses. While spleen and PPs serve to filter material in the blood and gastrointestinal tract, respectively, LNs are strategically situated in proximity to lymphatic and vascular branching points to effectively filter antigens and facilitate immune cell entry from surrounding tissues. Pioneering studies of human lymphoid organ development from the 1970s revealed that humans possess hundreds of lymph nodes variably positioned throughout the body, whereas mice have 22 LNs that always develop in the same distinct body sites 1-3. The hallmark feature of SLOs is the highly ordered compartmentalization of T cells, B cells and myeloid cells to generate optimal antigen-specific adaptive immune responses. Non-hematopoietic lymph node stromal cells (LNSCs), made up of both mesenchymal and endothelial cells, are paramount to maintaining LN integrity and function. LNSCs play a key role in LN organogenesis, maintenance of LN cellularity and compartmentalization and supporting immune responses. In this review, we will address recent advances elucidating the contribution of LNSCs, primarily mesenchymal cells, during immune system development and immune responses in adulthood, and highlight ongoing work that aims to expand our understanding of the heterogeneity that exists among LNSCs. LNSC coordination of LN organogenesis LN organogenesis begins as early as embryonic day (E)12.5-E13.5 in mice and weeks 8-11 of gestation in humans via the interactions of two key cell types, lymphoid tissue inducer (LTi) cells and lymphoid tissue organizer (LTo) cells, which, when brought together, form the primordial LN anlagen 1,4. LTi cells, belonging to the family of innate lymphoid cells (ILCs), originate from hematopoietic CD45 + Lin-IL-7Rα + Sca1 lo c-Kit lo common lymphoid progenitors (CLPs) in the mouse fetal liver and differentiate via expression of the transcription factors Id2 and RORγt. Mice deficient in Id2 or Rorγt are devoid of LTi cells and consequently lack LNs, highlighting the importance of LTi cells in this process 5,6. Differentiated LTi cells, also categorized as group 3 ILCs, are CD45 + CD3-RORγt + cells and are further defined by their expression of IL-7Rα, integrin α4β7, receptor activator of NF-κB (RANK) and its ligand RANKL, lymphotoxin-α1β2 (LT)

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Section: Box 1 | Tertiary Lymphoid Structures (Tls) and Tls In Diseasementioning

confidence: 99%

Lymph node stromal cells: cartographers of the immune system

Krishnamurty¹,

Turley²

2020

Nat Immunol

Self Cite

220

272

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“…On the one hand, FRCs regulate T cell function by attenuating self-reactivity through the presentation of peripheral tissue antigens and by reducing the proliferation of activated cells through the production of nitric oxide 5,6 . On the other hand, they are able to enhance immune responses by expressing costimulatory molecules, such as ICOSL, CD40 or IL-6, which promote IL-2 and TNF production by CD8 + T cells 51 . FRCs also respond to a variety of additional signals, including conduit fluid flow via the mechanosensitive ion channel Piezo1 52 , pathogen-associated molecular patterns 53 and activated T cells signals, like IL-17, which drive a metabolic reprograming of FRCs that promotes survival and proliferation 54 .…”

Section: Mesenchymal Cells In the Regulation Of Immunitymentioning

confidence: 99%

The mesenchymal context in inflammation, immunity and cancer

et al. 2020

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Mesenchymal cells are mesoderm-derived stromal cells that are best known for providing structural support to organs, synthesizing and remodeling the extracellular matrix (ECM) and regulating development, homeostasis and repair of tissues. Recent detailed mechanistic insights into the biology of fibroblastic mesenchymal cells have revealed they are also significantly involved in immune regulation, stem cell maintenance and blood vessel function. It is now becoming evident that these functions, when defective, drive the development of complex diseases, such as various immunopathologies, chronic inflammatory disease, tissue fibrosis and cancer. Here, we provide a concise overview of the contextual contribution of fibroblastic mesenchymal cells in physiology and disease and bring into focus emerging evidence for both their heterogeneity at the single-cell level and their tissue-specific, spatiotemporal functional diversity.

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“…Lymph node fibroblastic reticular cells (FRCs) have contradictory roles in immune responses, such as inhibition of T cell proliferation via nitric oxide (32) and T cell reprogramming towards memory T cells via IL6 (33). Albeit FRCs in LNs acquire transcriptional programs typically associated with tumor escape (34), we considered the possibility that immune evasion in Col1a2 Cre + IAb fl/fl mice resulted from MHCII deletion in FRCs.…”

Section: Resultsmentioning

confidence: 99%

Tumor MHCII immunity requires in situ antigen presentation by cancer-associated fibroblasts

Kerdidani

Goudevenou

Aerakis

et al. 2020

Preprint

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Author contributions: Conception and design study, M.T.; Development of methodology, M.T.;Acquisition of data, D.K., K.G., E.A., P.S., A.P. and M.T.; Analysis and interpretation of data, D.K., K.M.V., C.T., and M.T.; Providing human samples, I. ABSTRACTIn situ antigen presentation is required to sustain active proliferating CD4 + T cells in tumours and to help form memory CD8 + T cells, but the antigen presenting cells (APCs) and pathways involved remain elusive.Cancer associated fibroblasts (CAFs) are prominent stromal constituent of solid tumors. Current immunological dogma considers that CAFs facilitate tumour immune escape. A new subset of MHCII antigen presenting cancer-associated fibroblasts (apCAFs) has been described, but their function remains unknown. Here we report a previously unrecognized function of apCAFs in sustaining CD4 + T cells in primary human and murine lung tumours. In response to IFNγ and oxidative stress in tumours CAFs upregulated MHCII. Fibroblast-specific targeted ablation of MHCII induced a hypometabolic hypoproliferative state in CD4 + T cells, which impacted MHCII and MHCI immunity, accelerating tumor growth. apCAFs directly presented MHCII-peptide (MCHIIp) complexes to activate the TCRs of CD4 + T cell. Highthrough-put profiling and blocking assays unveiled a novel CAF to T cell communication pathway via complement 1q binding on membrane C1qbp. Thus, apCAFs sustain anti-tumor CD4 + T cells via MHCIIp-TCR and C1q-C1qbp binding. Our studies pave the way to the design of novel immunotherapeutic strategies that will harness apCAFs to help sustain T cells inside solid tumours. Statement of significanceThis work challenges the immunological dogma that dominant physiological significance in tumour specific immunity comes only through professional APCs, leading to the design of novel MHCII fibroblastdirected strategies to sustain endogenous or adoptively transferred CD4 + T cells within solid tumors.

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Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling

Cited by 63 publications

References 65 publications

Lymph node stromal cells: cartographers of the immune system

Lymph node stromal cells: cartographers of the immune system

The mesenchymal context in inflammation, immunity and cancer

Tumor MHCII immunity requires in situ antigen presentation by cancer-associated fibroblasts

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