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Cell Types

B cells

B cells are lymphocytes that are a cornerstone in humoral, that is, antibody-mediated immunity. They are distinguished by the expression of the BCR receptor which directly binds specific foreign antigens in their native form. The two major categories of B cells are plasma B cells which fully underwent maturation and differentiation to become effective antibody-producers and memory B cells which serve as a reminder of the first exposure and immune response to a pathogen and can quickly respond in the case of a subsequent exposure.

B cells need to go through a long and winding road of maturation that ensures they can produce an extremely diverse range of antibodies specific against virtually all possible foreign antigens while at the same time not reacting against antigens found on all normal, healthy cells. If the maturation pathway is altered or arrested, B cell lymphomas may develop.

References:

Roitt’s essential immunology Delves, Peter J; Roitt, Ivan M (Ivan Maurice)Roitt’s essential immunology. 12th ed. Chichester, West Sussex ; Hoboken, NJ : Wiley-Blackwell, 2011.

Amé-Thomas P, Tarte K. The yin and the yang of follicular lymphoma cellniches: role of microenvironment heterogeneity and plasticity. Semin Cancer Biol. 2014 Feb;24:23-32. doi: 10.1016/j.semcancer.

Contributed by Jan Misiak, STROMA ITN ESR at INSERM U917 – MICA.… Full article >

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T cells

T cells are lymphocytes that are a cornerstone in cell-mediated immunity. They are distinguished by the expression of the TCR receptor which recognizes antigens presented as processed peptides by the molecules of the major histocompatibility complex (MHC) displayed on various types of cells. While T cells come in different shapes and sizes, the two most frequent categories comprise helper T cells which express CD4 and cytotoxic T cells which express CD8. Each of these categories is further subdivided according to their function. Broadly speaking, the helper T cells assist and regulate other leukocytes in doing their jobs effectively, while the cytotoxic T cells destroy abnormal or virus-infected cells themselves.

In the context of stroma, helper and regulatory T cells are of special importance. For a number of cancers (follicular lymphoma in particular) the tumor niche consisting of immune cells, stromal cells and the malignant cells will either attenuate the protective function of helper T cells preventing them from mounting an efficient response or outright subvert them to support the growth of the tumor. Therefore, it is crucial to understand the interactions between stromal and lymphoid cells and how to influence them.

References:

Roitt’s essential immunology Delves, Peter J; Roitt, Ivan M (Ivan Maurice)Roitt’s essential immunology. 12th ed. Chichester, West Sussex ; Hoboken, NJ : Wiley-Blackwell, 2011.

Pangault C, Amé-Thomas P, Ruminy P, Rossille D, Caron G, Baia M, De Vos J,Roussel M, Monvoisin C, Lamy T, Tilly H, Gaulard P, Tarte K, Fest T. Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent T(FH)-B cell Full article >

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Dendritic Cells

Dendritic cells (DCs) are the sentinel cells of the immune system. In steady state and inflammatory conditions tissue migratory DCs constantly migrate from the periphery to draining lymph nodes to present self and foreign antigens to maintain peripheral tolerance or induce adaptive immunity, respectively [1,2].

Upon antigen encounter DCs undergo maturation, where they change function from antigen capturing cells to antigen presenting cells, and among other changes upregulate MHC class 2 and the CCL19/CCL21 chemokine receptor CCR7. Hereby tissue migratory DCs can enter afferent lymphatic vessels via CCL21 haptotactic gradients and migrate towards the draining lymph node [3]. From the lymph node subcapsular sinus (SCS) DCs enter the parenchyma in a CCR7 dependent way where they present the captured antigen to T-cells via MHC molecules [4, 5].

Lymphoid organ resident DCs in the lymph node are (opposed to tissue migratory DCs coming from the lymphatic system with peripheral antigen) associated with FRC produced conduits.  CD11b+ DCs are mainly found in the outer cortical areas surrounding B cell follicles, whereas CD8+CD205+ DCs are located in the deep cortical areas [5,6].

Lymphoid organ- resident DCs sample the conduit core for soluble antigens that are delivered from peripheral afferent lymphatic vessels and flow via the conduit system to the lumen of high endothelial venules (HEV) in the deep paracortex. Upon uptake and processing of small soluble antigens from the conduits lymphoid organ resident DCs present the captured antigen to naive T-cells long before any migratory DCs arrive in the lymph node [6].

Dendritic cell stromal … Full article >

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Innate Lymphoid Cells

Innate lymphoid cells (ILCs) are a heterogeneous population of immune cells with two defining characteristics: First, they belong to the lymphoid lineage and differentiate from the common lymphoid progenitor (CLP), dependent on IL-2Rγc signaling. Second, they lack antigen-specific receptors and therefore do not require the RAG proteins for development (Cortez V.S. et.al. 2015). ILCs are subdivided in 2 main groups, the cytotoxic ILCs or NK cells and the non-cytotoxic ILCs that correspond to the ILC1, ILC2 and ILC3.

In addition to their functions in lymphoid tissue development and metabolic homeostasis, innate lymphoid cells (ILCs) can orchestrate multiple antimicrobial effector functions at barrier surfaces in the context of exposure to viruses, bacteria, protozoa and helminths. Both natural killer (NK) cells and ILC1s produce interferon-γ (IFNγ) and contribute to protective immunity against viruses, intracellular bacteria and protozoan parasites. Production of type-2 cytokines (ILC2), including interleukin (IL)-4, IL-5, IL-9 and IL-13 promote alternative activation of macrophages, eosinophilia, goblet-cell hyperplasia and smooth-muscle contractility that contribute to expulsion of helminth parasites. ILC3s produce IL-17A, IL-22, lymphotoxin (LT) and tumour necrosis factor (TNF) and contribute to control of extracellular bacterial infection (D.Artis, H Spits 2015).

Image: (c) Nature, Artis D. and Spits, H.

Image: (c) Nature, Artis D. and Spits, H.

References:

Victor S. Cortez, Michelle L. Robinette, Marco Colonna, Innate lymphoid cells: new insights into function and development, Current Opinion in Immunology, Volume 32, February 2015, Pages 71-77

Artis D. , Spits H., The biology of innate lymphoid cells, Nature, 517,293–301 

Contributed by Bethania Cassani, STROMA ITN ESR Full article >

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Natural Killer cells

Natural Killer cells are large granular lymphoid-like cells with important functions in innate immunity as they are able to kill cells infected with intracellular pathogens or tumour cells. However unlike B or T lymphocytes, they lack antigen-specific receptors.

Reference:  Leave, O. , Natural killer cells: Maturation and function of NK cells, Nature Reviews Immunology 12, 150-151 (March 2012).

Contributed by Anne Thuery, STROMA ITN ESR at the University of YorkFull article >

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Neutrophils

Neutrophils (polymorophonuclear neutrophilic leukocytes) are innate immune cells that are the most abundant (40-75%) type of white blood cells. They clear a variety of pathogens by phagocytosis and destroy them in intracellular vesicles using enzymes and substances that degrade these microorganisms.

References: 

Kolaczkowska, E. , Kubes, P., Neutrophil recruitment and function in health and inflammation, Nature Reviews Immunology 13, 159-175 (March 2013).

Borko Amulic, Christel Cazalet, Garret L. Hayes, Kathleen D. Metzler, and Arturo Zychlinsky, Neutrophil Function: From Mechanisms to Disease Annual Review of Immunology, 30: 459-489 (April 2012).

Contributed by Anne Thuery, STROMA ITN ESR at the University of YorkFull article >

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Lymphoid Tissue inducer cells

Lymphoid Tissue inducer cells (LTi) are involved in the induction and function of lymphoid tissues.  Feotal LTi cells are essential for the development of lymph node anlagen. Adult LTi cells have roles in regulating T cell function in immune responses.

Key References:

Protocols:

Mouse Models:

Bioinformatics:Full article >

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Fibroblastic Reticular Cells

Fibroblastic reticular cells (FRCs) can be found in secondary lymphoid organs (SLOs) like the spleen, lymph nodes and Peyer’s patches. Within SLOs, the highest densities of FRCs are present in the T cell zones where they surround the central arterioles and high endothelial venules (1,2,3). Whereas a solely structural nature of FRCs by the formation of a fibroblastic reticulum was assumed historically, recent publications revealed a vast variety of functions (1,2): Besides of their role of maintaining the structure of SLOs and the delineation of the T cell compartment, FRC-derived cytokines and chemokines are important for the recruitment, survival and differentiation of naïve T cells (4). These chemokines include CCL19 and CCL21 which serve as chemoattractant for CCR7+ cells like T lymphocytes and dendritic cells (DCs) (5). Thus, FRCs are important players to recruit lymphocytes into SLOs and to establish the compartmentalization within the SLO.

Besides of these roles, FRCs shape SLO function and immune responses also in other ways: FRCs are also involved in antigen sampling as well as the collection and distribution of blood-borne molecules within the conduit system (6) . Moreover, FRCs support the interactions between T cells and DCs by providing a conduit system consisting of collagen-rich reticular fibres (7,8): LN-resident DCs adhere directly to FRCs in the T cell zone (9) and migrate along the FRC network by the expression of the C-type lectin receptor CLEC-2, the ligand of podoplanin expressed on FRCs (10). By these means FRCs facilitate interactions between professional antigen presenting cells (APCs) with T cells supporting … Full article >

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Follicular Dendritic Cells

Follicular Dendritic Cells (FDCs) are specialized stromal cell found in the B cell follicles. They are characterised by the expression of CXCL13, Complement Receptor and high levels of Prion Protein.

Key References:

Protocols:

Mouse Models:Full article >

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Marginal Reticular Cells

Marginal Reticular Cells (MRCs) are a subset of FRCs localized in the outer edge of the B cell follicles, just underneath the subcapsular sinus LECs. These cells are thought to be the adult counterpart of LTos, due to similarities in expression profile markers.  These cells express RANKL, MAdCAM-1, VCAM-1, CCL19, CXCL13 and podoplanin(1). Recent studies postulate that MRCs might be the precursors of FDCs(2).

Protocols:

-For flow cytometry MRCs are normally gated using a simple gate strategy: anti-CD31 and abti-gp38 disclose the main 4 stromal subsets (FRCs CD31-gp38+; LECs CD31+gp38+; BECs CD31+gp38- and DNCs CD31-gp38-). After gating on FRCs and using anti-MAdCAM-1 and anti-VCAM-1 antibodies we can see the MRC population which is MAdCAM-1+VCAM-1+.

-For immunofluorescence MRCs are normally visualised with an anti-RANKL antibody.

Mouse models:

-The CCL19 Cre EYFP enables to see EYFP+ cells in the MRCs region (but it is not exclusive to MRCs, FRCs are also EYFP+.

-The CCl19 Cre RANKL ff mouse, enables to study the influence of MRC RANKL, since it is KO in this model.

Key references:

1-Katakai, T. Marginal reticular cells: a stromal subset directly descended from the lymphoid tissue organizer. 2012 Front Immunol.

2-Meryem, J., et al., Fate mapping reveals origin and dynamics of lymph node follicular dendritic cells. The Journal of experimental medicine, 2014. 211(6)

Contributed by Olga Cordeiro, STROMA ITN ESR at IMBC StrasbourgFull article >

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Follicular Stromal Cells

Folluicular Stromal Cells (FSCs) are a specialized stromal cell that support B cells. Relatively little is known about these cells however they are thought to be precursor cells to Follicular Dendritic Cells.

Key References:

Protocols:

Mouse Models:Full article >

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Stromal Cell – Immune Cell interactions

Stroma: There are four types of stromal cells detailed, Fibroblastic Recticular Cells (FRCs) (or T cell zone Reticular Cells (TRCs)), Marginal Reticular Cells (MRCs), Follicular Dendritic Cells (FDCs) and Follicular Stromal Cells (FSCs) (or B cell stroma).

Tissue Inducing cells: There are two types of tissue inducing cells Lymphoid Tissue inducing cells (LTi cells) and Lymphoid Tissue initiating cells (LTin cells).

Lymphoid Cells: T lymphocytes (T cells), B lymphocytes (B cells) and Natural Killer (NK) Cellls invovled in lymphoid tissue formation.  Stromal cells regulate lymphiod cell function.

Other Innate Cells: Dendritic Cells (DCs) and Macrophages (Mac) function is regulated by stromal cells… Full article >

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