Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to infection.
2B4 is an inhibitory molecule found on immune cells. You may have heard of PD1, which cancer immunotherapy drugs block in order to re-energize the immune system. 2B4 appears to be similar; it appears on exhausted T cells after chronic viral infection, and its absence can contribute to autoimmunity.
In their new paper in Journal of Immunology, Mandy Ford, Craig Coopersmith and colleagues show that 2B4 levels are increased on certain types of T cells (CD4+ memory cells) in human sepsis patients and in a mouse model of sepsis called CLP (cecal ligation + puncture). Genetically knocking out 2B4 or blocking it with an antibody both reduce mortality in the CLP model. The effect of the knockout is striking: 82 percent survival vs 13 percent for controls.
How does it work? When fighting sepsis, 2B4 knockout animals don’t have reduced bacterial levels, but they do seem to have CD4+ T cels that survive better. CD4+ T cells, especially memory cells, get killed in large numbers during sepsis, and this is thought to contribute to mortality.
Taken together, our data indicate that 2B4−/− CD4+ T cells exhibit a more activated phenotype and have higher functionality during sepsis, a finding that could underlie the increased survival observed in 2B4-deficient mice.
The first author of the paper was Immunology and Molecular Pathogenesis graduate student Ching-wen Chen.
We’ve highlighted Ford and Coopersmith’s collaboration before; Ford originally became interested in 2B4 because of its role in immune rejection after organ transplant. Although other investigators have shown that 2B4 knockout has an influence on natural killer (NK) cells in viral infection, Ford and Coopersmith show that NK cells are not playing a role here.
In the discussion, the authors note that anti-PD1 drugs have been shown to improve sepsis survival in mice and have entered clinical trials. [Update: a check of clinicaltrials.gov says that the BMS study was terminated for business reasons.] There’s lots of room at the immunotherapy party — targeting PD1 might not be sufficient to revive critical cells, and 2B4 appears in the first 24 hours during sepsis, earlier than PD1 appears on immune cells.
We look forward to hearing the results of experiments designed to simulate adult humans’ more complicated immune systems.