The interaction of HLA class I molecules with their receptors and its effect on NK cells. (Doctoral thesis)

The role of HLA class I molecule interaction with their receptors in NK cell education is well established, but the molecular mechanism behind it as well as the role of these ligands on their receptors acquisition during NK cell development, are still unclear. Trying to give more insight to these questions, two different studies were performed on NK cells derived from patients presenting a genetic defect in the transporter associated with antigen processing (TAP), leading to a strongly reduced surface expression of HLA class I molecules.
In our first paper, the expression of HLA class I receptors (three killer immunoglobulin-like receptors (KIR) - KIR2DL1/DS1, KIR2DL2/3/DS2 and KIR3DL1 - NKG2A, CD8) and the maturation marker CD57 were dissected in seven TAP-deficient patients and a panel of healthy donors (HD). A comparison of the two NK cell statuses (healthy and TAP-deficient) showed a significant increase in HLA class I receptors’ co-expression in TAP-deficient compared to healthy NK cells. Functionally, hyporesponsiveness was confirmed for TAP-deficient NK cells: no cytotoxicity, degranulation nor IFN-γ production following co-culture with K562 cells. Only one patient presented functional NK cells with HLA class I receptors’ co-expression pattern being different form HD’s one.
In parallel, whole genome microarrays were performed on TAP-deficient vs HD’s NK cells, aiming to identify the maturation (from CD56bright to CD56dim) as well as cytotoxicity pathways which may be affected by HLA class I expression. The comparison of both statuses showed similar maturation processes (with different CD56bright and CD56dim gene profiles). Following 5 hours of CD56dim NK cells co-incubation with K562 cells, different gene clusters’ evolution lead to identical final profiles contradicting the significant functional difference.
Taken together, our data demonstrate a strong effect of HLA class I molecules on NK cell maturation and functionality as well as on their KIR repertoire formation.