Structure-function of the Immune System in the Spleen

Introduction

• The spleen is the largest secondary lymphoid organ, involved in immunological functions, hematopoiesis, and red blood cell clearance.
• It filters blood, facilitating interactions between APCs and lymphocytes.
• This review explores cell types, organization, and immunologic functions in the spleen, comparing differences between murine and human spleens.

Splenic Architecture

• Divided into red pulp (RP) and white pulp (WP), with the marginal zone (MZ) in rodents and the perifollicular zone in humans.
• WP is the primary immunologic region with less than 25% of tissue, while RP involves distinct immune functions.
• The spleen lacks afferent lymphatics; all cells and antigens enter via blood.

Mouse vs. Human Spleen

• Structural differences exist, especially in T cell zone (TCZ) and B cell zone (BCZ) organization.
• Advanced imaging techniques in humans are limited, making comparisons challenging.
• Marginal zone structures differ; murine MZ is well-defined, human PFZ less so.

White Pulp (WP)

• Acts as LN-like structures, demarcated by innate immune cells rather than a capsule.
• Antigens >60kDa delivered by MZ cells, no afferent lymphatics.
• T and B cells have distinct zones (TCZ and BCZ) influenced by chemokine gradients.

Red Pulp (RP)

• Extracts aged/dead/opsonized cells, surveys for pathogens/damage.
• Contains leukocytes with innate functions (neutrophils, monocytes, DCs, T cells, macrophages).
• Supports extramedullary hematopoiesis and cellular reserves.

Marginal Zone (MZ)

• Blood drains into MZ (mice) or PFZ (humans).
• MZB cells and macrophages capture/transport antigens to WP.
• MZM and MMM help filter blood and release lymphocytes into WP.

Bridging Channel

• Connects RP and WP; contains T cells and antibody-producing cells.
• Important for CD4+ T cell activation.

Immune Cell Function and Organization

Innate Immune Cells

• Myeloid cells with pattern recognition receptors (PRRs) activate T cells, cytokine secretion, and pathogen clearance.

Splenic DC Subsets

• DCs historically hard to classify; two main subsets:
  • cDC1s: XCR1+ CD8+, reside in WP or MZ/RP, activate CD8+ T cells.
  • cDC2s: SIRP+ CD11b+, reside in BC, activate CD4+ T cells.
• DC migration within spleen is essential for T cell priming.

Macrophages

• Tissue-resident phagocytes maintaining homeostasis and responding to infections.
• Four main subsets: MZM, MMM, RP macrophages, and tingible body macrophages.

Innate-like Lymphocytes

• NK and NKT cells, T cells, ILCs, and B-1 cells provide rapid cytokine responses and direct antigen presentation.

Adaptive Immune Cell Function

T and B Cells

• B-2 and follicular B cells produce antibodies, participate in germinal center reactions.
• T cells segregate into CD4+ (outer PALS) and CD8+ (central PALS) zones.

Immune Responses in the Spleen

Bacterial Infections

• Listeria monocytogenes: Highlights innate immune mechanisms in spleen.

Blood Transfusion

• Alloantigen response requires spleen; DCs primary APCs.

Parasitic Infections

• Plasmodium falciparum: Causes malaria, requires coordinated immune response.

Conclusions

• Understanding of immune cell positioning and migration is crucial for tailored responses.
• Techniques like intravital imaging offer insights but have limitations in studying human spleen.
• More research needed to compare human and murine spleen structures and functions.

Figures

1. Mouse and human splenic architecture.
2. Dynamic organization of the murine WP.