We have generated LAIR-1 -/- mice on a B6 background to study the in vivo function of LAIR-1. Phenotypic analysis of lymphoid organs did not show large differences between LAIR-1 +/+ and LAIR-1 -/- animals. We have observed a slight increase in the percentage of splenic B cells in the LAIR-1 -/- mice, along with a decrease in T cells, mostly because of a decrease in CD8 T cells. This probably does not result from abnormal trafficking of T lymphocytes, since LAIR-1 +/+ and LAIR-1 -/- T cells traffic equally to peripheral lymphoid organs. In the gut we have observed a slight increase of T cells in the LAIR-1 -/- mice, along with an increase in the NKG2D expression. In vitro experiments showed that OT-II LAIR-1-/- CD4 T cells proliferated less than the OT-II LAIR-1+/+ CD4 T cells when they are cultured with APC loaded with OT-II OVA peptide. To study the immune response in vivo, we have immunized the animals with TNP-OVA and found that class switching is affected in LAIR-1 -/- mice. These animals produced lower levels of IgG2a and IgG2b, while switching to IgG1 is not affected. By using T cell specific LAIR-1 -/- animals (CD4 Cre LAIR-1flox/flox), we confirmed that the defect in class switching is T cell specific. Previous investigators have published that mouse B cells do not express LAIR-1; however, recently we have found that marginal zone B cells are positive for LAIR-1 expression. Other preliminary results have shown that in the LAIR-1 -/- mice there are significant alterations in the recruitment of macrophages and eosinophils into the peritoneum in a model of chemical peritonitis, suggesting a role for LAIR-1 in the trafficking of these cell types towards sites of inflammation.? ? We showed that human neutrophils from peripheral blood express CD300a. To study expression during neutrophil development, we used the HL-60 differentiation model. We showed that CD300a expression is acquired during development and that cell surface expression increases very rapidly when neutrophils are stimulated with LPS and GM-CSF. This increase is the result of translocation of an intracellular pool of the receptor to the cell surface. This ready availability of CD300a is reminiscent of CTLA-4 and suggests that CD300a could play an important role in modulating neutrophil responses. Co-ligation of CD300a with the ITAM containing CD32a (FcRIIa) activation receptor inhibited CD32a mediated signaling, whereas it did not inhibit toll-like receptor (TLR)-4 mediated reactive oxygen species (ROS) production. Therefore, at least for human neutrophils, it seems that the inhibitory signals mediated by the CD300a receptor may be selective in their action.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000964-03
Application #
7732617
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2008
Total Cost
$481,729
Indirect Cost
City
State
Country
United States
Zip Code