The spleen in local and systemic regulation of immunity

Abstract

The spleen is the main filter for blood-borne pathogens and antigens, as well as a key organ for iron metabolism and erythrocyte homeostasis. Also, immune and hematopoietic functions have been recently unveiled for the mouse spleen, suggesting additional roles for this secondary lymphoid organ. Here we discuss the integration of the spleen in the regulation of immune responses locally and in the whole body and present the relevance of findings for our understanding of inflammatory and degenerative diseases and their treatments. We consider whether equivalent activities in humans are known, as well as initial therapeutic attempts to target the spleen for modulating innate and adaptive immunity.

Figure 1. Origins, behavioral activities and functions of splenic immune cell subsets

A. Schematic view of spleen’s anatomy. B. The cartoon depicts the location of several innate and adaptive immune cell components that are found in the resting spleen and can be involved in disease. The orange boxes identify the cells’ origins or the mechanisms that control their positioning or motility within the spleen. The white boxes identify generic functions attributed to the splenic immune cell subsets. Ag, antigen; CDP, Common DC progenitor; CR2, cannabinoid receptor 2; DC, dendritic cell; FDC, follicular DC; FO B cell, follicular B cell; GRK2, guanine nucleotide–binding protein–coupled receptor kinase-2; LTβ, lymphotoxin beta; LXR, liver X receptor; MZ, marginal zone; RA, retinoic acid, S1P1, sphingosine-1 phosphate-1. See also the Immunology image resource (http://www.cell.com/immunity/image_resource-spleen), which provides a collection of images of the spleen and its cellular constituents.

Figure 2. Splenic myeloid cell production and mobilization under inflammatory conditions

In the steady-state, circulating HSPCs do not seed the spleen and can re-engraft the bone marrow. Several inflammatory conditions including some cancers, myocardial infarction and atherosclerosis, however, induce HSPC survival and engraftment in the spleen, followed by local monocytic and granulocytic cell production. Some of the newly made cells may remain in their native tissue where they participate in the regulation of immune tolerance (see Fig 3) or relocate to distant tissues. The orange boxes identify molecular mechanisms that are known to orchestrate these sequential processes. AngII, angiotensin II; CMP, common myeloid progenitor; GM-CSF, granulocyte-macrophage-colony stimulating factor; GMP, granulocyte-macrophage progenitor; HDAC, histone deacetylase; HSC, hematopoietic stem cell; IL, interleukin; MDP, macrophage/DC progenitor; Rb, retinoblastoma.

Figure 3. The spleen is a site of immune tolerance induction

The spleen’s tolerogenic role depends on MZ cellular interactions between different macrophage subsets, CD8⁺ DCs, pDCs, inflammatory Ly6C^hi monocytes, NKT cells, TNF-related apoptosis inducing ligand (TRAIL)⁺ CD8⁺ T cells and CD4⁺Foxp3⁺ Tregs. Orange boxes show molecules involved with tolerance regulation. These include cytokines and soluble molecules (thrombospondin, TGFβ, IL-10), membrane-bound molecules (TRAIL and programmed death ligand 1 (PD-L1), enzymes (IDO, ARG, NOS, and 12/15 lipoxigenase (12/15 LO)) and reactive oxygen species (ROS). These circuits operate: i) in steady-state by sensing apoptotic remnants released by privileged tissues such as the eye (ACAID) or during normal cell turn-over in conventional tissues; and ii) under inflammatory conditions such as trauma, acute and chronic inflammation including cancer, which result in increased loads of apoptotic materials and microvesicles, as well as stimulation of splenic myelopoiesis (see Fig 2).