Fibroblastic Reticular Cells From Lymph Nodes Attenuate T Cell Expansion by Producing Nitric Oxide

Abstract

Adaptive immune responses are initiated when T cells encounter antigen on dendritic cells (DC) in T zones of secondary lymphoid organs. T zones contain a 3-dimensional scaffold of fibroblastic reticular cells (FRC) but currently it is unclear how FRC influence T cell activation. Here we report that FRC lines and ex vivo FRC inhibit T cell proliferation but not differentiation. FRC share this feature with fibroblasts from non-lymphoid tissues as well as mesenchymal stromal cells. We identified FRC as strong source of nitric oxide (NO) thereby directly dampening T cell expansion as well as reducing the T cell priming capacity of DC. The expression of inducible nitric oxide synthase (iNOS) was up-regulated in a subset of FRC by both DC-signals as well as interferon-γ produced by primed CD8+ T cells. Importantly, iNOS expression was induced during viral infection in vivo in both LN FRC and DC. As a consequence, the primary T cell response was found to be exaggerated in Inos −/− mice. Our findings highlight that in addition to their established positive roles in T cell responses FRC and DC cooperate in a negative feedback loop to attenuate T cell expansion during acute inflammation.

Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes

“…For example, fibroblastic reticular cells in lymph nodes suppress T cell activation and expansion to maintain peripheral tolerance (21)(22)(23). Fibroblasts also modulate inflammation such as that seen with inflammatory arthritis, psoriasis, inflammatory bowel disease, and cancer by recruiting, activating, inhibiting, or maintaining leukocytes in tissues (24, 36, 37).…”

“…Under basal conditions, they produce homeostatic CCL19, CCL21, and IL-7, which support T cell accumulation and survival (19,20). Then, following activation, they suppress T cell responses via the production of nitric oxide (21)(22)(23). In some autoimmune inflammatory disorders such as rheumatoid arthritis (RA), fibroblasts are major producers of IL-6 as well as a range of other cytokines and chemokines (24)(25)(26).…”

Re-thinking the functions of IgA+plasma cells

“…C T cells, [131][132][133][134][135] endogenous iNOS activity was shown to be required for the polarization of Th17 and Treg cells, 134,136 suggesting that the magnitude and localization of iNOS activity and NO production is critical for the priming and polarization of the Ag-specific T cell pool. Moreover, iNOS-deficient animals have been shown to have lower serum and intestinal IgA and serum IgG2b.…”

Arginine Cools the Inflamed Gut

“…Nitric oxide produced by iNOS in inflammatory monocytes and dendritic cells regulates inflammatory cytokine production, cell differentiation, and survival (31)(32)(33). In addition, the regulated release of NO by nonhematopoietic stromal cells controls the expansion of activated T cells (34)(35)(36), and T cell-intrinsic iNOS activity regulates polarization of antigen-specific CD4 ϩ T helper cells (37)(38)(39). Moreover, expression of iNOS by intestinal B cells is critical for immunoglobulin A class switch recombination and intestinal immunohomeostasis at steady state and upon intestinal infection (40).…”