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Since there were no phenotypic or functional alterations in the transferred effector T cells to correspond with the delay in weight loss observed in CD45RAGKO upon colitis, we next assessed whether innate cell cytokines were altered upon colitis development. Figure 4. Strikingly, these results demonstrate that even though CD45RAGKO mice have delayed progression and development of systemic inflammation, the development of intestinal inflammation upon T cell transfer colitis was equal to that of the RAGKO mice and this was dissociated from the systemic disease.
This demonstrates that CD45 plays an important role in systemic spread of inflammation. We hypothesized that T cells in the CD45RAGKO mice had either been induced to become more pro-inflammatory and restricted to the intestine due to local intestinal cues or accumulated in the CD45RAGKO colon upon colitis induction and were unable to spread systemically thereby delaying inflammation and weight loss.
We found no evidence for effector T cell accumulation in the colon Figure 4. This was induced by the transferred T cells, as there was no difference in the myeloid cell populations prior to colitis induction Figure 4. This observation also suggested a feedback of inflammation induced by the T cells or T cell cytokines on bone marrow progeniors to make more monocytes in the CD45RAGKO mice in T cell transfer colitis. Splenomegaly and anemia are often associated with colitis development in both mice and humans. Post colitis induction at the RAGKO endpoint, there was an increase in spleen weight between the control mice and the colitis mice for both genotypes but 93 Figure 4.
These results suggest that CD45 on erythroblasts promotes the maturatution in to erythrocytes prior to and post T cell colitis. Therefore, we wanted to evaluate further the progenitors of erythrocytes in control and colitis mice and assess whether these cells could be limiting systemic inflammation in the CD45RAGKO mice in T cell transfer colitis. It has been reported that upon T cell transfer colitis, GMPs are increased at the expense of MEPs, which are reduced in order to generate more inflammatory intestinal myeloid cells Griseri et al. Erythropoiesis develops in the bone marrow from MEPs to eventually become mature erythrocytes Figure 4.
The development of erythrocytes goes through several stages where the final stages 98 Figure 4. As erythrocytes mature, the expression of CD45 decreases. A Erythropoiesis: the maturation process of erythrocytes from MEPs. Erythrocytes along with reticulocytes and acidophilic end-stage erythroblasts are a heterogeneous population within Erythroblast C. A Ery. B Ery.
Regulatory T-lymphocytes in asthma
Interestingly, this is when the expression of CD45 decreases upon erythroblast maturation at the erythroblast B and C stages Figure 4. This implies that the downregulation of CD45 expression on early erythroblasts is needed for the proper maturation of erythrocytes and that in the absence of CD45, the signal to differentiate but not proliferate is compromised. These results show that CD45 is needed for Figure 4. The development of IBD is not just limited to intestinal inflammation as other extraintestinal complications may result Levine and Burakoff, A common extraintestinal complication of IBD is the development of anemia that can result from EPO unresponsiveness, insufficient production of erythroid progenitors and iron malabsorption.
In animal models of colitis the degree of weight loss is often associated with the severity of gut inflammation. However, in this report, we show that weight loss is disconnected to intestinal inflammation. We show that the absence of CD45 on innate immune cells leads to equal inflammation due to increased myeloid cells in the LP and a lack of DCs in the mLNs that may contribute to the systemic spread of disease.
CD45 is a protein tyrosine phosphatase and is known best as a negative and positive regulator of SFKs in adaptive and innate immune cells. CD45 is only expressed on early erythroid progenitors and its expression gradually decreases as erythroblasts mature into erythrocytes Craig et al. While it has been reported that CD45 deficient bone marrow progenitors generate increased erythroid colonies in response to EPO compared to control cells, the functional consequence of this phenomena in vivo had not been examined Irie-Sasaki et al.
In addition, we show that upon inflammation induced by T cell transfer colitis, the enhanced numbers of these cells in the spleen and bone marrow of CD45RAGKO mice are maintained and MEP numbers are not decreased. EPO is also well established to act on erythroid progenitors and enhance erythrocytes in vivo Ridley et al. In addition, progenitors of erythroid cells, MEPs are downregulated upon inflammation Griseri et al. Taken together, these various studies all suggest that the erythroid lineage and factors that promote this lineage such as EPO have an anti-inflammatory effect on the immune system.
JAK2 Neubauer et al. In vivo upon disease, aspects of these results in vitro are recapitulated. Interestingly, a report by Voedisch et al. These results suggested that the mLNs are a barrier shielding other systemic compartments from DC bound bacterial antigens Griffin et al. It is therefore a possibility that the enhanced numbers of CD45 deficient intestinal myeloid cells act to limit the inflammation to the gut and prevent the systemic dissemination of disease, allowing for prolonged overall survival upon T cell transfer colitis.
In support of this, Griseri et al. The enhanced GMPs are progenitors to intestinal myeloid cells that promote inflammation Griseri et al. Overall, our results show a novel role for CD45 in promoting the maturation of erythroblasts into mature erythrocytes. Our results also show that upon inflammation induced by T cell transfer colitis, CD45 restrains the numbers of intestinal myeloid cells limiting intestinal inflammation.
These results highlight the role CD45 plays in vivo on individual cell types in order to regulate inflammation. Our findings also suggest new avenues for potential therapeutics for anaemia, cachexia and intestinal inflammation. Therefore, the comparable T cell numbers in the intestine was surprising. The dramatic increase of this gut homing molecule compared to WT mice suggests that CD45 deficient T cells have enhanced gut homing.
Interestingly, these results counter the perception that the T cells that do develop in CD45 deficient mice are anergic or non-functional Kishihara et al. It was concluded that CD45KO mice are not able to mount an appropriate cytotoxic T lymphocyte response due to abrogation of footpad swelling after local infection with lymphocytic choriomeningitis virus Kishihara et al.
This may be due to insufficient CD45KO T cell numbers but the T cells may intrinsically be able to make sufficient or exacercabated pro-inflammatory cytokines, which was not assessed in this study. The T cells that do develop in the CD45 deficient mice are shown to have a more activated phenotype with enhanced expression of the activation markers, CD44 and LFA-1 Kong et al. However, there were notable differences in cell populations and cytokine production in the intestine. Previous studies have demonstrated that in an inflammatory and a homeostatic environment, RA induced homing molecules on effector T cells and Tregs Coombes et al.
Mortha et al.
Conversely, Basu et al. In addition, Basu et al. Therefore, it will be imperative to determine whether IL-1 production is altered or whether another inflammatory cytokine such as IL regulates RA production in the CD45 deficient gut. Determining how CD45 regulates cytokine production will illuminate further how cells communicate with each other in a complex cytokine environment upon inflammation and why certain inflammatory situations yield distinct pathways of effector T cell function. The enhanced number of CD45 deficient inflammatory myeloid cells that may overcome the suppressive ability of CD45 deficient erythroblasts may account for these contradictory results.
In fact, Jackson et al. While Elahi et al.
Notably, the percentage of cells expressing CD45 steadily decreases as erythrocytes mature Figure 4. In CD45 deficient mice, the accumulation of cells is at the erythroblast A and B stage, so as CD45 expression decreases. It is evident that the downregulation of CD45 is necessary for the downregulation of immature erythroblasts but how this is regulated is not clear. The role of CD45 in vivo upon intestinal inflammation was also established in the projects here and CD45 was shown to regulate pro-inflammatory cytokine production by T cells, ILCs and myeloid cells and the maturation of immature RBCs.
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In the absence of CD45, the presence or absence of an adaptive immune system determined disease severity. This highlights the bi-directional communication between the adaptive and innate immune system. However, still nothing is known about the impact of CD45 on type 2 immunity. Furthermore, the CD45 deficient T cells at other mucosal sites such as the lung and skin have not also been analyzed. Therefore, it is of interest to find the roles of CD45 during type 2 inflammation such as helminth infection or allergy. Finally, the projects here also reveal new avenues of therapeutics for intestinal diseases.
By targeting CD45, several cytokines may be affected at once providing a more complete treatment for disease. Furthermore, these results reveal the complexity of the intestinal immune system and how easily the proper communication between immune cells can be broken down or exacerbated. The absence of CD45 does not just affect the function of one cell-type but causes a domino effect on multiple cells and their functions.
Inflammatory bowel disease. N Engl J Med , Agace, W. T-cell recruitment to the intestinal mucosa. Trends in immunology 29, Curr Opin Cell Biol 12, Ahern, P. The interleukin axis in intestinal inflammation. Immunological reviews , Interleukin drives intestinal inflammation through direct activity on T cells. Immunity 33, Akashi, K.
The Regulations of Gene Expressions by 1α,25(OH)2D3 in Patients with Inflammatory Bowel Diseases
A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature , Ando, T. MAdCAM-1 expression and regulation in murine colonic endothelial cells in vitro. Inflammatory bowel diseases 11, Annacker, O. Essential role for CD in the T cell-mediated regulation of experimental colitis. J Exp Med , Annunziato, F. Phenotypic and functional features of human Th17 cells.
Bain, C. The monocyte-macrophage axis in the intestine. Cellular immunology , Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal immunology 6, Basu, R. Nature immunology 16, Beagley, K. Differences in intraepithelial lymphocyte T cell subsets isolated from murine small versus large intestine.