Inherited defects in lymphocyte cytotoxic activity.
The granule-dependent cytotoxic activity of lymphocytes plays a critical role in the defense against virally infected cells and tumor cells. The importance of this cytotoxic pathway in immune regulation is evidenced by the severe and often fatal condition, known as hemophagocytic lymphohistiocytic syndrome (HLH) that occurs in mice and humans with genetically determined impaired lymphocyte cytotoxic function. HLH manifests as the occurrence of uncontrolled activation of T lymphocytes and macrophages infiltrating multiple organs. In this review, we focus on recent advances in the characterization of effectors regulating the release of cytotoxic granules, and on the role of this cytotoxic pathway in lymphocyte homeostasis and immune surveillance. Analysis of the mechanisms leading to the occurrence of hemophagocytic syndrome designates gamma-interferon as an attractive therapeutic target to downregulate uncontrolled macrophage activation, which sustains clinical and biological features of HLH.
Institut National de la Santé et de la Recherche Médicale (INSERM), U768, 75015 Paris, France.
Jana
J
Pachlopnik Schmid
Jana P
JP
Schmid
Marjorie
M
Côte
Mickaël M
MM
Ménager
Agathe
A
Burgess
Nadine
N
Nehme
Gaël
G
Ménasché
Alain
A
Fischer
Geneviève
G
de Saint Basile
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D040582:Inheritance Patterns; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology / Q000628:therapy; D008262:Macrophage Activation / Q000235:genetics; D051379:Mice; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D022142:Secretory Vesicles / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D007371:Interferon-gamma