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It has been known for some time that single mutant nude or CD40T mice have apparently normal numbers of cells in the precursor compartments of bone marrow and the mature B cell compartments of the periphery. X-linked immunodeficiency (XID) mice are deficient only in some of the slgM+slgD+ B cells. We have investigated further the contributions of the xid mutation, of the T cell deficiency of nude and of the inability of CD40T B cells to cooperate with T cells in the generation of the precursor and the mature B cell compartments in mice. Double mutant XIDInu and XIDlCD4OT mice have precursor B cell compartments that are no more deficient than the single mutant XID mice. However, the peripheral B cell compartments of both XIDInu and XIDlCD40T are even more deficient than those of single mutant XID mice. While 10% of the peripheral B cells of wild-type or CD40T, one-third of XID and half of XIDInu mice turn over rapidly, as many as threequarters of those in XIDlCD40T are short-lived. Total numbers of slgM+slgD+ B cells in the spleen are at best 1615% of normal mice at 6-8 weeks of age in XID, XIDInu and XIDICD40T mice. They remain that low at 3 months of age in XIDICD40T mice, while in XID mice these peripheral B cells slowly build up in numbers with age. As expected, double mutant XIDlCD40T mice do not respond to the T-dependent antigen keyhole limpet hemocyanin. Only the responses to the T-independent type I antigen, TNP-lipopolysaccharide (LPS), appear to be normal. In vitro, their splenic B cells respond poorly to LPS or to IgM-specific antibody in either the absence or presence of cytokines. Most notably, serum IgM, lgG2b and lgG3 levels are severely depressed, while IgG1, lgG2a and IgA levels are

Interleukin-10 acts directly on CD45RBlo but not CD45RBhi cells to control colitis upon transfer into Rag1-deficient recipients.The role of direct IL-10 signaling in different T cell subsets is not well understood. To address this, we generated transgenic mice expressing a dominant-negative IL-10 receptor specifically in T cells (CD4dnIL-10Rα). We found that Foxp3-depleted CD45RBlo (regulatory T cell [Treg cell]–depleted CD45RBlo) but not CD45RBhi CD4+ T cells are controlled directly by IL-10 upon transfer into Rag1 knockout (KO) mice. Furthermore, the colitis induced by transfer of Treg cell–depleted CD45RBlo CD4+ T cells into Rag1 KO mice was characterized by reduced Th1 and increased Th17 cytokine messenger RNA levels in the colon as compared with the colitis induced by transfer of CD45RBhi T cells. In contrast to the CD45RBhi transfer colitis model, in which IL-22 is protective, we found that T cell–derived IL-22 was pathogenic upon transfer of Treg cell–depleted CD45RBlo T cells into Rag1 KO mice. Our results highlight characteristic differences between colitis induced by naive (CD45RBhi) and memory/effector (Treg cell–depleted CD45RBlo) cells and different ways that IL-22 impacts inflammatory bowel disease.

Cytokines play a major role in maintaining lymphocyte homeostasis under both steady-state and inflammatory conditions. Unregulated lymphocytes in steady-state conditions can lead to autoimmunity, whereas during inflammation they can cause excessive tissue damage. Regulatory cytokines function in combination with other environmental signals to properly modulate the function and the extent of lymphocyte activation. Many recent studies have highlighted the importance of regulatory cytokines in controlling the differentiation and function of lymphocytes under steady-state and inflammatory conditions, as well as minimizing tissue damage.

Chronic viral infections lead to CD8+ T cell exhaustion, characterized by impaired cytokine secretion. Presence of the immune-regulatory cytokine IL-10 promotes chronicity of Lymphocytic Choriomeningitis Virus (LCMV) Clone 13 infection, while absence of IL-10/IL-10R signaling early during infection results in viral clearance and higher percentages and numbers of antiviral, cytokine producing T cells. IL-10 is produced by several cell types during LCMV infection but it is currently unclear which cellular sources are responsible for induction of viral chronicity. Here, we demonstrate that although dendritic cells produce IL-10 and overall IL-10 mRNA levels decrease significantly in absence of CD11c+ cells, absence of IL-10 produced by CD11c+ cells failed to improve the LCMV-specific T cell response and control of LCMV infection. Similarly, NK cell specific IL-10 deficiency had no positive impact on the LCMV-specific T cell response or viral control, even though high percentages of NK cells produced IL-10 at early time points after infection. Interestingly, we found markedly improved T cell responses and clearance of normally chronic LCMV Clone 13 infection when either myeloid cells or T cells lacked IL-10 production and mice depleted of monocytes/macrophages or CD4+ T cells exhibited reduced overall levels of IL-10 mRNA. These data suggest that the decision whether LCMV infection becomes chronic or can be cleared critically depends on early CD4+ T cell and monocyte/macrophage produced IL-10., PLoS Pathogens, 9 (11), ISSN:1553-7374, ISSN:1553-7366