Mobilizing killer cells to combat CIA

“Blockade of the NKG2A inhibitory receptor on NK cells 'releases the brakes' in these cells and allows them to destroy arthrogenic T cells without the risk of untoward side effects associated with antibodies specific for activating receptors,” says Harvey Cantor. Now published in Proceedings of the National Academy of Sciences, the data Cantor describes show that enhancing the activity of natural killer (NK) cells to destroy activated autoimmune T cells arrests the progression of collagen-induced arthritis (CIA), and could be a new approach to tackle rheumatoid arthritis.

...injection of anti-NKG2A antibody ... reduced numbers of T_FH and T_H17 cells, but not T_H1 or T_H2 cells...

“Current antibody-based approaches to deplete pathogenic T cells use antibodies directed at activating receptors on T cells,” continues Cantor. “Many of these antibodies can partially stimulate T cells, resulting in activation-induced untoward side effects, including 'cytokine storms'.” Key to avoiding such problems is defining which T helper (T_H) lineages are aberrantly activated in disease, and finding ways to target them specifically. To identify the T_H cells that mediate CIA pathogenesis, Cantor and colleagues transferred various collagen-reactive T_H cell subsets and B cells into mice deficient in NK cells, and examined the resultant joint pathology. Interaction of follicular T_H (T_FH) cell-dependent autoantibody production with proinflammatory actions of type 17 T_H (T_H17) cells was thereby implicated in the disease process. Noting that transfer of activated immune cells failed to elicit disease in NK-cell-sufficient mice, and having found previously that blocking the inhibitory signal delivered by the NKG2A receptor, as Cantor puts it, “unleashes NK cell killing of activated, autoreactive T cells,” (see further reading), the researchers hypothesized that enhancing NK cell activity through use of an anti-NKG2A antibody might be a new therapeutic approach for rheumatoid arthritis. Indeed, injection of the antibody into collagen-immunized mice reduced numbers of T_FH and T_H17 cells, but not T_H1 or T_H2 cells, and ameliorated disease.

“The advantage of this approach over current strategies is that it depends on directed lysis of a small subpopulation of autoreactive T cells, rather than a general effect on the T cell repertoire,” says Cantor. He adds that NKG2A is conserved between mice and humans, and anti-NKG2A therapy has entered clinical trials.