Static and dynamic components synergize to form a stable survival niche for bone marrow plasma cells.

In the bone marrow (BM), memory plasma cells (PCs) survive for long time periods in dedicated microenvironmental survival niches, resting in terms of proliferation. Several cell types, such as eosinophils and reticular stromal cells, have been reported to contribute to the survival niche of memory PCs. However, until now it has not been demonstrated whether the niche is formed by a fixed cellular microenvironment. By intravital microscopy, we provide for the first time evidence that the direct contacts formed between PCs and reticular stromal cells are stable in vivo, and thus the PCs are sessile in their niches. The majority (∼ 80%) of PCs directly contact reticular stromal cells in a non-random fashion. The mesenchymal reticular stromal cells in contact with memory PCs are not proliferating. On the other hand, we show here that eosinophils in the vicinity of long-lived PCs are vigorously proliferating cells and represent a dynamic component of the survival niche. In contrast, if eosinophils are depleted by irradiation, newly generated eosinophils localize in the vicinity of radiation-resistant PCs and the stromal cells. These results suggest that memory PC niches may provide attraction for eosinophils to maintain stability with fluctuating yet essential accessory cells.

Interleukin-7 links T lymphocyte and intestinal epithelial cell homeostasis.

Interleukin-7 (IL-7) is a major survival factor for mature T cells. Therefore, the degree of IL-7 availability determines the size of the peripheral T cell pool and regulates T cell homeostasis. Here we provide evidence that IL-7 also regulates the homeostasis of intestinal epithelial cells (IEC), colon function and the composition of the commensal microflora. In the colon of T cell-deficient, lymphopenic mice, IL-7-producing IEC accumulate. IEC hyperplasia can be blocked by IL-7-consuming T cells or the inactivation of the IL-7/IL-7R signaling pathway. However, the blockade of the IL-7/IL-7R signaling pathway renders T cell-deficient mice more sensitive to chemically-induced IEC damage and subsequent colitis. In summary, our data demonstrate that IL-7 promotes IEC hyperplasia under lymphopenic conditions. Under non-lymphopenic conditions, however, T cells consume IL-7 thereby limiting IEC expansion and survival. Hence, the degree of IL-7 availability regulates both, T cell and IEC homeostasis.

Commensal microflora and interferon-gamma promote steady-state interleukin-7 production in vivo.

IL-7 is a major regulator of lymphocyte homeostasis; however, little is known about the mechanisms that regulate IL-7 production. To study Il7 gene regulation in vivo, we generated a novel IL-7-reporter mouse, which allows the non-invasive quantification of Il7 gene activity in live mice and, additionally, the simultaneous activation/inactivation of target genes in IL-7-producing cells. With these IL-7-reporter mice, we identify thymus, skin and intestine as major sources of IL-7 in vivo. Importantly, we show that IFN-gamma and the commensal microflora promote steady-state IL-7 production in the intestine. Furthermore, we demonstrate that the blockade of IFN-gamma signaling in intestinal epithelial cells strongly reduces their IFN-gamma-driven IL-7 production. In summary, our data suggest a feedback loop in which commensal bacteria drive IFN-gamma production by lymphocytes, which in turn promotes epithelial cell IL-7 production and the survival of IL-7-dependent lymphocytes.

IFN-gamma receptor signaling regulates memory CD8+ T cell differentiation.

IFN-gamma regulates multiple processes in the immune system. Although its antimicrobial effector functions are well described, less is known about the mechanisms by which IFN-gamma regulates CD8(+) T cell homeostasis. With the help of adoptive T cell transfers, we show in this study that IFN-gammaR signaling in CD8(+) T cells is dispensable for expansion, contraction, and memory differentiation in response to peptide vaccination. In contrast, host IFN-gammaR signaling counterregulates CD8(+) T cell responses and the generation of effector memory T cell processes, which are partially regulated by CD11b(+) cells. Similar to vaccination-induced proliferation, host IFN-gammaR signaling limits the expansion of naive CD8(+) T cells and their differentiation into effector memory-like T cells in lymphopenic mice. In contrast to peptide vaccination, IFN-gammaR signaling in CD8(+) T cells contributes to memory fate decision in response to lymphopenia, an effect that is fully reversed by high-affinity TCR ligands. In conclusion, we show that host IFN-gammaR signaling controls the magnitude of CD8(+) T cell responses and subsequent memory differentiation under lymphopenic and nonlymphopenic conditions. In contrast, IFN-gammaR signaling in CD8(+) T cells does not affect cell numbers under either condition, but it directs memory fate decision in response to weak TCR ligands.

Innate immune cells contribute to the IFN-gamma-dependent regulation of antigen-specific CD8+ T cell homeostasis.

IFN-gamma has a dual function in the regulation of T cell homeostasis. It promotes the expansion of effector T cells and simultaneously programs their contraction. The cellular mechanisms leading to this functional dichotomy of IFN-gamma have not been identified to date. In this study we show: 1) that expansion of wild-type CD8+ T cells is defective in IFN-gamma-deficient mice but increased in IFN-gammaR-deficient mice; and 2) that contraction of the effector CD8+ T cell pool is impaired in both mouse strains. Furthermore, we show that CD11b+ cells responding to IFN-gamma are sufficient to limit CD8+ T cell expansion and promote contraction. The data presented here reveal that IFN-gamma directly promotes CD8+ T cell expansion and simultaneously induces suppressive functions in CD11b+ cells that counter-regulate CD8+ T cell expansion, promote contraction, and limit memory formation. Thus, innate immune cells contribute to the IFN-gamma-dependent regulation of Ag-specific CD8+ T cell homeostasis.