Differing Activities of Homeostatic Chemokines CCL19, CCL21, and CXCL12 in Lymphocyte and Dendritic Cell Recruitment and Lymphoid Neogenesis

Abstract

Despite their widespread expression, the in vivo recruitment activities of CCL19 (EBV-induced molecule 1 ligand chemokine) and CXCL12 (stromal cell-derived factor 1) have not been established. Furthermore, although CXCL13 (B lymphocyte chemoattractant) has been shown to induce lymphoid neogenesis through induction of lymphotoxin (LT)α1β2, it is unclear whether other homeostatic chemokines have this property. In this work we show that ectopic expression in pancreatic islets of CCL19 leads to small infiltrates composed of lymphocytes and dendritic cells and containing high endothelial venules and stromal cells. Ectopic CXCL12 induced small infiltrates containing few T cells but enriched in dendritic cells, B cells, and plasma cells. Comparison of CCL19 transgenic mice with mice expressing CCL21 (secondary lymphoid tissue chemokine) revealed that CCL21 induced larger and more organized infiltrates. A more significant role for CCL21 is also suggested in lymphoid tissues, as CCL21 protein was found to be present in lymph nodes and spleen at much higher concentrations than CCL19. CCL19 and CCL21 but not CXCL12 induced LTα1β2 expression on naive CD4 T cells, and treatment of CCL21 transgenic mice with LTβR-Fc antagonized development of organized lymphoid structures. LTα1β2 was also induced on naive T cells by the cytokines IL-4 and IL-7. These studies establish that CCL19 and CXCL12 are sufficient to mediate cell recruitment in vivo and they indicate that LTα1β2 may function downstream of CCL21, CCL19, and IL-2 family cytokines in normal and pathological lymphoid tissue development.

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…Given that the early clustering of LTi cells within the embryo is dependent on CXCL13, and that CXCL13 is detected early in the developing lymph nodes of LT α ‐deficient mice,46, 47 this chemokine represents a key initiator of lymphoid organogenesis that functions upstream of LT β R signalling. At ELFs, CXCL13 and CCL21 regulate B‐cell and T‐cell infiltration and segregation at ELFs 48, 49, 50. Similarly, chemokines CCL19 and CXCL12 drive lymphocyte recruitment and the positioning of follicular DCs, B cells and plasma cells at germinal centres 48.…”

“…At ELFs, CXCL13 and CCL21 regulate B‐cell and T‐cell infiltration and segregation at ELFs 48, 49, 50. Similarly, chemokines CCL19 and CXCL12 drive lymphocyte recruitment and the positioning of follicular DCs, B cells and plasma cells at germinal centres 48. Here, an elegant cooperation between CXCL12 and CXCL13 directs the movement of B cells from the dark zone into the light zone as they mature into antibody‐secreting plasma cells 51.…”

“…Transgenic overexpression of Cxcl13 in the pancreas induces the production of LT α 1 β 2 by B cells that is required for the development of ELFs that feature T‐cell and B‐cell segregation with HEV formation 49. CCL19 and CCL21 similarly drive the expression of LT α 1 β 2 on naive CD4 T helper cells 48. Hence, homeostatic chemokines are an integral feature of ELF development, organization and function.…”

“…Nevertheless, there appears to be some hierarchy among these chemokines in their ability to drive ectopic lymphoneogenesis. For example, transgenic overexpression of Ccl21 promotes the development of larger lymphoid follicles than those that emerge in response to Ccl19 48. Transgenic Ccl21 expression also promotes the development of ELFs that display higher cellular organization than Ccl19 .…”

“…Transgenic Ccl21 expression also promotes the development of ELFs that display higher cellular organization than Ccl19 . Interestingly, ectopic Cxcl12 expression induces ELFs that contain few T cells but are enriched for follicular DCs, B cells and plasma cells 48. Therefore, as well as determining the size and degree of cellular organization within ELFs, the relative expression of homeostatic chemokines at inflammatory lesions will also determine the cellular composition of ELFs.…”