HVEM interactions inhibit innate immunity to regulate tissue injury and bacterial infection: A novel role for co-inhibition

The current model of co-regulation suggests that co-inhibition is critical for contraction of an adaptive immune response. In the following study, I present evidence to support the novel finding that co-inhibition can also act early in the immune response. I found that B and T lymphocyte attenuator (BTLA) co-inhibitory signaling is required to temper early inflammation and limit tissue injury because BTLA-/- mice exhibited reduced survival and increased early serum cytokine secretion to NKT-dependent Con A challenge as compared to wild type mice. This was due to BTLA inhibition of NKT cells, as BTLA-/- liver mononuclear cells or purified NKT cells from mice are hyper-responsive to anti-CD3, Con A, and alpha-GalCer stimulation and secrete higher levels of TNF-alpha, IFN-gamma, IL-2, and IL-4. Recently, our lab reported the HVEM-BTLA interaction inhibits the very early responders to Listeria monocytogenes intracellular bacterial infection. However, whether this was due to inhibition of the innate response was unclear. Lymphocyte-independent responses against LM infection were evaluated and demonstrate that HVEM, but not BTLA, inhibits host innate defense against bacterial infection, as HVEM/Rag DKO mice, but not BTLA/Rag DKO, survived significantly longer and had lower liver titers of LM than Rag-/- mice. My data show that this is due in part to HVEM inhibition of phagocytic monocyte frequency. I argue here that the previously unappreciated role of coinhibition in early immune responses is essential to maintain a balance between protecting against pathogens and protecting the host against immunopathology.