The inhibitory receptors on NK cells and CTLs are upregulated in adult and adolescent patients with secondary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) includes primary HLH (pHLH) and secondary HLH (sHLH). Mutations that cause abnormal functions in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) are frequently identified in pHLH. However, why NK cells and CTLs exhibit abnormal functions in sHLH remains unclear. Here, we demonstrated that NK cells in sHLH exhibited a high expression of inhibitory receptor NKG2A and a low expression of activating receptor NKG2D. Besides, the expression of HLA-E on lymphocyte, the adaptor of NKG2A on NK cells, was elevated in sHLH. Moreover, CTLs in sHLH patients expressed a higher level of functional exhaustion markers PD-1, TIM-3 and LAG-3 as well as a lower secretion of IFN-γ and CD107a upon stimulation. In addition, the expression of MHC-I on lymphocytes was decreased. Taken together, our study indicates a potentially pathological mechanism of sHLH and may open up new avenues for the development of immunotherapies against sHLH.