Elimination in vivo of developing T cells by natural killer cells

Area of Science:

• Immunology
• Cell Biology

Background:

• Natural killer (NK) cells use inhibitory receptors, like Ly49, to detect absent self-major histocompatibility complex (MHC) class I on target cells.
• NK cell activation requires both a lack of inhibitory signals and the presence of activating ligands on target cells.
• While NK cell-mediated rejection of MHC class I-deficient bone marrow (BM) grafts is known, in vivo targeting of specific cellular subsets by NK cells remains unclear.

Purpose of the Study:

• To investigate the in vivo targeting of specific cellular subsets by natural killer (NK) cells.
• To understand the impact of NK cell toxicity on the development of MHC class I-deficient thymocytes after bone marrow grafting.

Main Methods:

• Grafting MHC class I-negative bone marrow (BM) into MHC class I-positive hosts.
• Analyzing thymocyte development and cellular phenotypes in the presence of NK cells.
• Utilizing retroviral transduction to reconstitute MHC expression (H2-K(b)) in BM precursors.

Main Results:

• Development of MHC class I-negative thymocytes was delayed due to NK cell toxicity post-BM grafting.
• Persistent double-positive thymocytes exhibited a T cell receptor-deficient phenotype but generated mature, MHC class I-deficient lymphocytes.
• MHC class I-deficient CD8 T cells were functional but remained susceptible to NK cell toxicity.
• Retroviral transduction to restore H2-K(b) expression fully normalized thymic development.

Conclusions:

• NK cells actively surveil and eliminate MHC class I-deficient thymocytes in vivo, impacting thymic development.
• MHC class I expression is crucial for protecting developing T cells from NK cell-mediated toxicity.
• Restoration of MHC class I expression rescues normal thymic development and T cell maturation, confirming NK cell surveillance mechanisms.