Plasmacytoid dendritic cells: important players in human kidney allograft rejection.

Plasmacytoid dendritic cells are a unique dendritic cell subset that bridges innate and adaptive immune responses. They release high amounts of type I interferons in response to viral and bacterial infection. Plasmacytoid dendritic cells are thought to act as key players in renal allograft rejection, but the underlying mechanisms are unclear. Ruben et al. now demonstrate that granulocyte/macrophage colony-stimulating factor produced by renal epithelial cells is important to induce plasmacytoid dendritic cell maturation and indirect antigen presentation triggering allogeneic immune responses.

Chondroitin sulfate activates B cells in vitro, expands CD138+ cells in vivo, and interferes with established humoral immune responses.

Glycosaminoglycans have anti-inflammatory properties and interact with a variety of soluble and membrane-bound molecules. Little is known about their effects on B cells and humoral immune responses. We show that CS but not dextran or other glycosaminoglycans induces a pronounced proliferation of B cells in vitro compared with TLR4 or TLR9 ligands. With the use of inhibitors and KO mice, we demonstrate that this proliferation is mediated by the tyrosine kinases BTK and Syk but independent of CD44. Antibodies against Ig-α or Ig-ß completely block CS-induced B cell proliferation. Injection of CS in mice for 4-5 days expands B cells in the spleen and results in a marked increase of CD138(+) cells in the spleen that is dependent on BTK but independent of CD4(+) T cells. Long-term treatment with CS for 14 days also increases CD138(+) cells in the bone marrow. When mice were immunized with APC or collagen and treated with CS for up to 14 days during primary or after secondary immune responses, antigen-specific humoral immune responses and antigen-specific CD138(+) plasma cells in the bone marrow were reduced significantly. These data show that CD138(+) cells, induced by treatment with CS, migrate into the bone marrow and may displace other antigen-specific plasma cells. Overall, CS is able to interfere markedly with primary and fully established humoral immune responses in mice.

Basophils support the survival of plasma cells in mice.

We have previously shown that basophils support humoral memory immune responses by increasing B cell proliferation and Ig production as well as inducing a Th2 and B helper phenotype in T cells. Based on the high frequency of basophils in spleen and bone marrow, in this study we investigated whether basophils also support plasma cell survival and Ig production. In the absence of basophils, plasma cells of naive or immunized mice rapidly undergo apoptosis in vitro and produce only low amounts of Igs. In contrast, in the presence of basophils and even more in the presence of activated basophils, the survival of plasma cells is markedly increased and continuous production of Igs enabled. This effect is partially dependent on IL-4 and IL-6 released from basophils. Similar results were obtained when total bone marrow cells or bone marrow cells depleted of basophils were cultured in the presence or absence of substances activating basophils. When basophils were depleted in vivo 6 mo after immunization with an Ag, specific Ig production in subsequent bone marrow cultures was significantly reduced. In addition, depletion of basophils for 18 d in naive mice significantly reduced the number of plasma cells in the spleen. These data indicate that basophils are important for survival of plasma cells in vitro and in vivo.

CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes.

Fibrocytes are collagen-type-I-producing cells that arise at low frequency from hematopoietic cells. We have analyzed in mice which leukocyte subsets are required for generation of fibrocytes and show that murine fibrocytes develop from the subpopulation of CD11b(+) CD115(+) Gr1(+) monocytes under the control of CD4(+) T cells. In the absence of CD4(+) T cells, differentiation of fibrocytes was markedly reduced in vitro and in vivo. In the presence of CD4(+) T cells, the characteristics of T-cell activation critically determined development of fibrocytes. Polyclonal activation of CD4(+) T cells induced the release of soluble factors that completely prevented the outgrowth of fibrocytes and could be identified as IL-2, TNF, IFN-gamma, and IL-4. Application of IL-2 and TNF significantly reduced the appearance of fibrocytes and the severity of fibrosis in the model of unilateral ureteral obstruction. In contrast, activation of CD4(+) T cells in the presence of calcineurin inhibitors, but not mTOR inhibitors, markedly enhanced the outgrowth of fibrocytes and renal deposition of collagen I. Taken together, we show that differentiation of fibrocytes is critically dependent on CD4(+) T cells and that the context of T-cell activation determines whether development of fibrocytes is supported or blocked. Our data may have implications for prevention of organ fibrosis in autoimmune diseases and transplantation.