Immune function and dysfunction are determined by lymphoid tissue efficacy

Abstract

Lymphoid tissue returns to a steady state once each immune response is resolved, and although this occurs multiple times throughout life, its structural integrity and functionality remain unaffected. Stromal cells orchestrate cellular interactions within lymphoid tissue, and any changes to the microenvironment can have detrimental outcomes and drive disease. A breakdown in lymphoid tissue homeostasis can lead to a loss of tissue structure and function that can cause aberrant immune responses. This Review highlights recent advances in our understanding of lymphoid tissue function and remodelling in adaptive immunity and in disease states. We discuss the functional role of lymphoid tissue in disease progression and explore the changes to lymphoid tissue structure and function driven by infection, chronic inflammatory conditions and cancer. Understanding the role of lymphoid tissues in immune responses to a wide range of pathologies allows us to take a fuller systemic view of disease progression.

Keywords: Fibroblastic reticular cells; Homeostasis; Lymphoid tissue; Stromal cells.

Fig. 1.

Fibroblastic reticular cells (FRCs) are central in maintaining the lymph node niche. (1) Lymph node FRCs produce the chemokines CCL19 and CCL21 to recruit dendritic cells (DCs) and T cells that express CCR7. Secretion of IL-7 by FRCs drives the survival of T cells within the lymph node microenvironment. (2) CD4⁺ T cells express lymphotoxin (LT), which interacts with the LTβ receptor (LTβR) on FRCs and thus provides the survival factor for FRCs. (3,4) FRCs have immunoregulatory roles: they can activate regulatory T cells (Tregs) through the secretion of TGF-β (3) or induce peripheral tolerance of CD8⁺ T cells through the interaction between major histocompatibility complex (MHC) and T-cell receptor (TCR) (4). (5) FRCs can produce CXCL13, which can recruit lymphoid tissue inducers (LTi) and B cells. B-cell survival is also driven by the interaction between the surface B-cell activating factor (BAFF) on FRCs and the BAFF receptor (BAFFR) on B cells. TGF-βR, TGF-β receptor.

Fig. 2.

Breakdown of homeostasis in organ tissue and lymph nodes drives graft versus host disease (GVHD). (1) Upon allogenic transplantation, donor cells, such as cytotoxic T cells, target host tissue in organs such as the intestine and initiate tissue damage. (2) Innate cells of the host, including neutrophils, monocyte-derived DCs, and donor CD11b⁺ and CD103⁺ DCs migrate to the lymph node. (3) DC recruitment increases the trapping of T cells in the lymph node. (4,5) T cells become activated against cognate host antigens and migrate to the intestine, where they drive damage and remodelling. (6) FRCs in the lymph node secrete TGF-β to activate Tregs and suppress the aberrant activation of T cells. (7) Tregs can migrate to the intestine, modulate the microenvironment, and further exacerbate tissue damage and remodelling. (8) Loss of peripheral tolerance is driven by the aberrant activation of T cells, which target the FRC network. LTi, lymphoid tissue inducer; LTo, lymphoid tissue organiser.

Fig. 3.

FRCs drive the formation and maintenance of the niche in lymph nodes and in tertiary lymphoid structures. (1) Lymph node anlagen formation is driven by the retinoic acid (RA) released by nerves binding to the RA receptor (RAR) on the embryonic lymphoid tissue organiser (eLTo) cells. eLTo cells secrete CCL21 and IL-7, leading to the recruitment and survival of LTi precursors (LTi₀), which express IL-7 receptor (IL-7R), CCR7 and RAR. LTi₀ cells secrete IL-22 and IL-17, inducing eLTo differentiation. (2) Tertiary lymphoid structure (TLS) development is not fully understood, but occurs through a phenotypic change of stromal precursors or pericytes proximal to blood vessels. Multiple factors are involved in TLS formation, including IFN-γ [from activated T and natural killer (NK) cells] or inflammatory mediators such as IFN-α or IL-17, while a contribution of RA from neurons cannot be excluded. (3) LTo cells secrete CXCL13, CCL21, CCL19 and IL-7 to recruit LTi₄ cells. RANKL–RANK and lymphotoxin–LTβR binding between LTi₄ and LTo cells causes the activation of LTo cells. (4) TLS niche formation is driven by podoplanin⁺ (PDPN⁺) FRCs producing CXCL13 and CCL21 to recruit T and B cells. (5,6) FRCs are central for niche maintenance in lymph nodes and TLSs by interacting with leukocytes. How TLS stroma is replenished is unknown; however, the presence of mesenchymal precursors or LTi/ILC3 cells cannot be excluded. Th, T helper.