Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells

Abstract

Interleukin 7 is essential for the survival of naive T lymphocytes. Despite its importance, its cellular source in the periphery remains poorly defined. Here we report a critical function for lymph node access in T cell homeostasis and identify T zone fibroblastic reticular cells in these organs as the main source of interleukin 7. In vitro, T zone fibroblastic reticular cells were able to prevent the death of naive T lymphocytes but not of B lymphocytes by secreting interleukin 7 and the CCR7 ligand CCL19. Using gene-targeted mice, we demonstrate a nonredundant function for CCL19 in T cell homeostasis. Our data suggest that lymph nodes and T zone fibroblastic reticular cells have a key function in naive CD4(+) and CD8(+) T cell homeostasis by providing a limited reservoir of survival factors.

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

“…The view that T-cell fitness is not a digital state of either survival or death but rather dynamic state is consistent with concepts of competition for survival resources. Such a view is also consistent with the recent insights into the high mobility of lymphocytes within the 3-dimensional structure of the lymph node [38,39], and that the source of IL-7, and likely other survival factors within these structures, is not homogeneously distributed, but rather focal and from specific cell types [11]. In such a context, a dynamic fitness model of T-cell survival would permit integration and interpretation of multiple and likely sporadic survival cues.…”

“…Lymphocytes are unlikely to have unfettered access to the multiple environmental cues required for their survival, but rather receive such signals on a sporadic basis. Consistent with this view, chemokines direct T cells to sites of IL-7 production within lymph nodes [11]. Thus, the homeostatic fitness of a T cell and consequently whether it lives or dies in a given homeostatic context may depend on how frequently it receives survival signals such as IL-7 and how long the cell can persist in the absence of such survival signalling.…”

On the move: endocytic trafficking in cell migration

“…An analogous mechanism has been recently identified for CCR7-driven dendritic cell and lymphocyte migration in mammalian lymphoid organs [11]. Here the atypical chemokine CCRL1/ACKR4 expressed by lymphatic endothelial cells lining the ceiling of the subcapsular sinus [11], scavenges CCL21, which is produced by stromal cells in the T zone of lymph nodes [12], to form the chemokine gradient. Additional atypical chemokine receptors have been described, which in contrast to classical chemokine receptors do not transmit signals resulting in chemotaxis [13], however, their role in generating chemokine gradients and their potential regulation by endocytosis have not yet been addressed.…”

Expansion of Cortical and Medullary Sinuses Restrains Lymph Node Hypertrophy during Prolonged Inflammation

“…Blocking VEGFR2 and VEGFR3 signaling had remarkably little effect on the expansion of FRCs (Fig. 3A) and presumably minimal alterations in the expression of CCL21 and CXCL12, which are chiefly produced by FRCs (48)(49)(50). However, arrested lymphangiogenesis arising from a blockade of VEGFR2 and VEGFR3 signaling abrogated restoration of lymphocyte egress and underpins that lymphangiogenesis, specifically that of cortical and medullary sinuses, plays an important part in the re-establishment of lymphocyte egress during protracted inflammation.…”