Negative regulation of T cell activation by placental protein 14 is mediated by the tyrosine phosphatase receptor CD45.
CD45 is the major protein tyrosine phosphatase receptor on T cell surfaces that functions as both a positive and a negative regulator of T cell receptor (TCR) signaling. Although CD45 is required for the activation of TCR-associated Src family kinases, it also dephosphorylates phosphoproteins involved in the TCR-signaling cascade. This study links CD45 to the inhibitory activity of placental protein 14 (PP14), a major soluble protein of pregnancy that is now known to be a direct modulator of T cells and to function by desensitizing TCR signaling. PP14 and CD45 co-capped with each other, pointing to a physical linkage between the two. Interestingly, however, the binding of PP14 to T cell surfaces was not restricted to CD45 alone, with evidence showing that PP14 binds to other surface molecules in a carbohydrate-dependent fashion. Notwithstanding the broader molecular binding potential of PP14, its interaction with CD45 appeared to have special functional significance. Using transfected derivatives of the HPB. ALL mutant T cell line that differ in CD45 expression, we established that the inhibitory effects of PP14 are dependent upon the expression of intact CD45 on T cell surfaces. Based upon these findings, we propose a new immunoregulatory model for PP14, wherein one of its surface molecular targets, CD45, mediates its T cell inhibitory activity, accounting for the intriguing capacity of PP14 to elevate TCR activation thresholds and thereby down-regulate T cell activation.
Rachmilewitz
Jacob
J
Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem 91120, Israel. rjacob@hadassah.org.il
Borovsky
Zipora
Z
Riely
Gregory J
GJ
Miller
Robin
R
Tykocinski
Mark L
ML
D002118:Calcium / Q000378:metabolism; D002241:Carbohydrates / Q000737:chemistry; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D015536:Down-Regulation; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D000071816:Glycodelin; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D017493:Leukocyte Common Antigens / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation; D008856:Microscopy, Fluorescence; D009154:Mutation; D009844:Oligosaccharides / Q000494:pharmacology; D011257:Pregnancy Proteins / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D013997:Time Factors
D002241:Carbohydrates; D003432:Cross-Linking Reagents; D000071816:Glycodelin; D006023:Glycoproteins; D009844:Oligosaccharides; C045246:PAEP protein, human; D011257:Pregnancy Proteins; D017493:Leukocyte Common Antigens; D002118:Calcium