Title

The effects of hemizygous CD45 expression on the Faslgld/gld autoimmune syndrome

Date of Completion

January 2002

Keywords

Biology, Genetics|Biology, Cell|Health Sciences, Pathology|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Mice homozygous for the Faslgld/gld mutation cannot initiate apoptosis via the Fas/Fasl pathway and develop an autoimmune disease characterized by the accumulation of CD4/CD8 (DN) T cells, and a progressive T cell anergy. These DN T cells express a high molecular weight isoform of the membrane PTPase CD45 (B220). We have produced a Faslgld/gld mouse strain with only one functional CD45 allele (CD45+/−, Faslgld/gld) in order to explore the role that CD45 plays in the lymphoaccumulation and proliferative capacity of the DN T cells. ^ The central findings in this study suggest that the elevated specific activity of CD45 plays a role in the induction or maintenance of the anergic phenotype of DN T cells and therefore, the autoimmune syndrome of Faslgld mice. In an environment where autoreactive T cells are unable to undergo apoptosis via the Fas/Fasl pathway CD45 isoform expression changes along with specific activity in such a way that extracellular signals can no longer elicit intracellular responses. Hence, by reducing the enzymatic activity of CD45 cells that were previously fated to become anergic undergo apoptosis via an unknown non-Fas/Fasl pathway.^ The focus of this research has been a detailed analysis of the immune function and signaling capabilities of mice that expresses only one allele of CD45 in the context of an autoimmune background. This hemizygous expression of CD45 reduces its activity by roughly one half allowing us to assess the role of increased CD45 specific activity on the function of DN T cells directly. ^ In contrast to CD45+/+, Faslgld/gld mice, CD45+/−, Faslgld/gld mice display a tenfold reduction in the DN T cell population, have decreased levels of anti-DNA antibodies, and total serum Ig. However, enriched DN T cell populations remain unresponsive to mitogenic stimulation, but do display altered patterns of tyrosine phosphorylation. These data indicate that CD45 is essential to the accumulation of DN T cells in Faslgld/gld mice and implicates CD45 as a component of the process of deletion that normally governs the composition of the T cell population. ^