Defective CTLA-4 cycling pathway in Chediak-Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, also known as CD152) has been shown to play a major role in the regulation of T cell activation. Its membrane expression is highly regulated by endocytosis and trafficking through the secretory lysosome pathway. Chediak-Higashi syndrome (CHS) is an inherited disorder caused by mutations in the lysosomal trafficking regulator gene, LYST. It results in defective membrane targeting of the proteins present in secretory lysosomes, and it is associated with a variety of features, including a lymphoproliferative syndrome with hemophagocytosis. The murine equivalent of CHS, beige mice, present similar characteristics but do not develop the lymphoproliferative syndrome. We show herein that CTLA-4 is present in enlarged, abnormal vesicles in CHS T cells and is not properly expressed at the cell surface after T cell activation, whereas its surface expression is not impaired. It is therefore proposed that the defective surface expression of CTLA-4 by CHS T cells is involved in the generation of lymphoproliferative disease. This observation may provide insight into the role of CTLA-4 in humans.
Barrat
F J
FJ
Institut National de la Santé et de la Recherche Médicale, U 429, Hôpital Necker Enfants-Malades, 75743 Paris Cédex 15, France.
Le Deist
F
F
Benkerrou
M
M
Bousso
P
P
Feldmann
J
J
Fischer
A
A
de Saint Basile
G
G
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002609:Chediak-Higashi Syndrome / Q000235:genetics*; D003594:Cytoplasmic Granules / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D018796:Immunoconjugates; D047908:Intracellular Signaling Peptides and Proteins; D007962:Leukocytes; D008213:Lymphocyte Activation / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism*; D033921:Vesicular Transport Proteins
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D047908:Intracellular Signaling Peptides and Proteins; C102161:LYST protein, human; C491133:Lyst protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; D033921:Vesicular Transport Proteins; D054353:Perforin; D000069594:Abatacept