CD8αα+MHC Class II+ Cell with the Capacity To Terminate Autoimmune Inflammation Is a Novel Antigen-Presenting NK-like Cell in Rats

Abstract

Discovery of immune tolerance mechanisms, which inhibit pre-existing autoimmune inflammation, may provide us with new strategies for treating autoimmune diseases. We have identified a CD8αα+MHC-II+ cell with professional APC capacity during our investigation on spontaneous recovery from autoimmune glomerulonephritis in a rat model. This cell actively invades inflamed target tissue and further terminates an on-going autoimmune inflammation by selective killing of effector autoreactive T cells. Now, we showed that this cell used a cytotoxic machinery of Ly49s+ NK cells in killing of target T cells. Thus, this CD8αα+MHC-II+ cell was a dually functional antigen presenting NK-like (AP-NK) cell. Following its coupling with target T cells through antigen presentation, killing stimulatory receptor Ly49s6 and co-receptor CD8αα on this cell used non-classic MHC-I RT1CE16 on the target T cells as a ligand to initiate killing. Thus, activated effector T cells with elevated expression of RT1CE16 were highly susceptible to the killing by the CD8αα+ AP-NK cell. Granule cytolytic perforin/granzyme C from this cell subsequently mediated cytotoxicity. Thus, inhibition of granzyme C effectively attenuated the killing. As it can recognize and eliminate effector autoreactive T cells in the inflamed target tissue, CD8αα+ AP-NK cell not only represents a new type of immune cell involved in immune tolerance, but also is a potential candidate for developing a cell-based therapy for pre-existing autoimmune diseases.

Natural killer cells in cancer biology and therapy

“…Besides established cytotoxic cNK cells, it has been demonstrated that NK cells could differentiate into antigen-presenting NK (AP-NK) cells [ 83 ], helper NK (NKh) cells [ 84 ] and regulatory NK (NKreg) cells, each defined by surface molecules and individual functions. A new CD8αα + MHC-II + phenotype with professional APC capacity was considered to represent unusual AP-NK cells, recognizing and eliminating autoreactive T cells and finally killing them like cNK cells [ 85 ]. Human plasmacytoid dendritic cells (DCs) activated by the preventive vaccine FSME upregulate CD56 expression on their surface [ 86 ]; in mice, B220 + CD11c int NK1.1 + cells have antigen-presenting capacity like DC, hence their name interferon-producing killer DC [ 87 , 88 ].…”

Group 1 innate lymphoid cells are involved in the progression of experimental anti-glomerular basement membrane glomerulonephritis and are regulated by peroxisome proliferator-activated receptor α

“…Therefore, this population of ILC1s differs from conventional NK cells. Wu et al 38 reported the identification of a CD8aa þ major histocompatibility complex class II þ cell with both antigen-presenting functions and NK-like cytotoxicity. In their anti-GBM GN rat model, these cells infiltrated into glomeruli on days 35 to 40 after disease induction and suppressed inflammation by inducing apoptosis in effector CD4 þ T cells.…”