Lymphotoxin-sensitive microenvironments in homeostasis and inflammation

Abstract

Stromal cell microenvironments within lymphoid tissues are designed to support immune cell homeostasis and to regulate ongoing immune responses to pathogens. Such stromal cell networks have been best characterized within lymphoid tissues including the spleen and peripheral lymph nodes, and systems for classifying stromal cell phenotypes and functions are emerging. In response to inflammation, stromal cell networks within lymphoid tissues change in order to accommodate and regulate lymphocyte activation. Local inflammation in non-lymphoid tissues can also induce de novo formation of lymphoid aggregates, which we term here "follicle-like structures." Of note, the stromal cell networks that underpin such follicles are not as well characterized and may be different depending on the anatomical site. However, one common element that is integral to the maintenance of stromal cell environments, either in lymphoid tissue or in extra-lymphoid sites, is the constitutive regulation of stromal cell phenotype and/or function by the lymphotoxin (LT) pathway. Here we discuss how the LT pathway influences stromal cell environments both in homeostasis and in the context of inflammation in lymphoid and non-lymphoid tissues.

Keywords: chemokine; fibroblastic reticular cell; follicle-like structures; follicular dendritic cell; lymph node; lymphotoxin.

FIGURE 1

Stromal cell elements in the lymph node under lymphotoxin control during homeostasis and inflammation. The LT pathway is critical for the proper maintenance and function of various stromal cell elements in the LN. During homeostasis, chemokine production by FDC in the primary follicle is required for B cell positioning (1). LTβR signaling in endothelial cells of HEV is also required for the expression of sulfotransferases that promote the proper glycosylation of PNAd (2). During inflammation, the LN becomes enlarged, stromal cells acquire new functions, and increased vascularization occurs (not depicted). In addition, clusters of B and T cells aggregate within germinal centers during T-dependent immune responses, and highly differentiated FDC within the GC environment require LTβR signaling (3). To facilitate the output of plasma cells that emerge from these GC reactions, remodeling of the medullary region has been shown to occur (4).