Regulation Of The Immune Response By The Inositol Phosphatase SHIP

National Institute Of Allergy And Infectious Diseases

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Abstract

To avoid the pleiotropic effects of the SHIP germline deletion, we have generated conditional knockout mice with deletion of SHIP restricted to T cell, B cells, or macrophages. We believe these mice are the optimal system to address SHIPs intrinsic roles in a variety of immune cells. Our data show that SHIP is essential for the regulation of Th1/Th2 responses by T cells, in determining antibody affinity and isotype switching in B cells, and for the formation of suppressor macrophages that can limit IL17 and other inflammatory responses. By comparing phenotypes of these mice with that of the total SHIP deletion in SHIP-null mice, we have been able to assess the impact that myeloid dysregulation can inflict on the lymphocyte activation status. We have found discordance between the phenotype of SHIP-null mice and that of mice with lymphocyte-restricted deletion of SHIP, indicating that the activated phenotype of lymphocytes in SHIP-null mice occurs as a secondary effect of the dysregulation of SHIP-deficient myeloid cells. We have confirmed this hypothesis by the analysis of mice with SHIP deletion restricted to the macrophagegranulocyte lineage. These mice were generated by breeding SHIP floxed mice to mice with Cre recombinase expression driven by the LysMcre promoter 37. LysMcre SHIP conditional mice develop a myeloproliferative pathology that reduces their lifespan, although the severity of disease is not as dire as in SHIP null mice (Tarasenko and Bolland, unpublished). One possible explanation as to why the LysMcre deletion of SHIP does not completely recapitulate the pathology observed in SHIP-null mice is that the deletion of SHIP in LysMcre occurs in already differentiated macrophages but not in earlier precursors that could be potentially be more pathogenic in the absence of SHIP. Another possible explanation is that cells other than macrophages and granulocytes contribute to the overall phenotype in SHIP-null mice. Deletion of SHIP in macrophages not only leads to myeloid hyperproliferation, but also to lymphocyte activation as a secondary effect. LysMcre SHIP conditional mice develop splenomegaly with a large number of activated lymphocytes. We determined that T cells in these mice are biased toward the Th17 phenotype and expand the regulatory population (T.Tarasenko and B. Bolland, unpublished data). This result explains the phenotype observed in T cells from SHIP-null mice as resulting from overt macrophage hyperactivity as opposed to a clear role for SHIP in T cell development. Specifically, our data is consistent with the view that SHIP-deficient macrophages are hypersensitive to growth factor stimulation (e.g. CSF) and release inflammatory cytokines (IL6 and others) that promote T cell IL17 bias. Additionally, we observed that LysMcre SHIP conditional mice lack the type of suppressor macrophages that has been reported to keep immunogenic dendritic cells in check 53. Further analysis of these mice with conditional deletion of SHIP in macrophages will give insight into how spontaneous activation of myeloid cells can influence the entire immune response and lead to a chronic inflammatory pathology.