טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentShivtiel Shoham
SubjectThe Involvement of CD19 and CD45 in B-Lymphocytes
Development: Tolerance, Selection and Allelic
Exclusion
DepartmentDepartment of Medicine
Supervisor Professor Doron Melamed


Abstract

In the B cell lineage, receptor expression and signaling are critical to promote development, maturation and tolerance. All signals are modified by response regulators such as CD19 and CD45, which lower the signaling threshold required for B cell activation. We studied the role of CD19 and CD45 molecules in regulating BCR signaling threshold required for establishment of allelic exclusion, positive selection and immune tolerance. In 3-83Tg mice, where B cell repertoire is limited by the transgene, CD19 deficiency results in impaired maturation and developmental arrest of immature B cells. We found that immature 3-83Tg CD19-/- B cells expressing compromised receptors fail to impose L chain allelic exclusion and undergo intensive V(D)J recombination. These cells also failed to undergo positive selection and to survive when adoptively transferred into normal recipients. However, elevation of BCR expression levels, obtained by transgene homozygosity, effectively compensated for the compromised BCR, lacking of CD19, and completely restored BCR-mediated Ca2+ influx, allelic exclusion establishment and positive selection. Our results suggest that CD19 molecule regulates BCR signaling threshold required for establishment of L chain allelic exclusion, positive selection and maturation of developing B cells.

In contrast to CD19 deficiency, 3-83Tg B-lymphocytes deficient of CD45 undergo normal development, maturation and selection and were able to impose allelic exclusion. In response to encountering self-antigen we found that immature 3-83Tg CD45-/- B cells efficiently elevated recombinase genes and undergo receptor editing. These results show that in our experimental system, lack of CD45 dose not abrogate the establishment of self-tolerance.