What’s new

Major achievements

Life and death at the cellular level is central to the existence of multicellular organisms. While homeostatic apoptosis provides a continuous supply of newly generated cells for the normal turnover of tissues and development of organs, cell death following infection or injury represents a new danger signal, which must be interpreted by the innate immune system. The Blander Lab studies how phagocytes, the most important innate immune cells, sense and integrate these signals from dying cells and microbes and respond to them. Generally, we investigate the logic through which these signals are decoded in mounting an inflammatory or reparative response and shaping adaptive immunity. We also study how the logic is distorted in chronic inflammatory disorders and cancer, especially at mucosal surfaces such as the gut.

One of our seminal contributions was toward establishing phagosomal autonomy. We showed that individual phagosomes — the intracellular compartments that engulf microbes or dying cells — function as independent “decision-making” units. Their activity is driven by the nature of the cargo within and not the activation state of the entire phagocyte. This provides a cellular basis for the exquisite sensitivity of the immune system in detecting pathogenic insults, as microbes internalized within a phagosome are sensed by phagosomal membrane Toll-like receptors, leading to the induction of phagosomal cross-presentation of microbial antigens on MHC class I. Conceptually, this opened the door for the rational design of vaccine platforms, whereby antigen and adjuvant are targeted into the same phagosomal compartment to achieve superior immune responses, as demonstrated in preclinical testing. Indeed, we leveraged this approach in preclinical cancer models by delivering bacterial proteins into the phagosomes of tumor cells, which potently primed anti-tumor CD8 T cell immunity. We have applied this knowledge to deliver bacterial proteins into the phagosomes of tumor cells in preclinical cancer models, resulting in potent priming of anti-tumor CD8 T cell immunity.

We also revealed that apoptotic cells dying through infection drive phagocytes to secrete a complex combination of inflammatory and anti-inflammatory mediators. Such a milieu programs Th17-type protective immunity, promoting optimal defense and repair of infected tissues. In contrast, phagocytosis of homeostatically apoptotic cells initiates immunosuppressive transcriptional programs in phagocytes, many of which are associated with susceptibility to chronic inflammatory diseases such as inflammatory bowel disease.

Another major advance was the discovery that the innate immune system discriminates live from dead microbes via vita-PAMPs—molecular signatures of viable bacteria. . We identified two key examples: bacterial messenger RNA (mRNA), a vita-PAMP that partners with lipopolysaccharide from Gram-negative bacteria to activate the NLRP3 inflammasome and drive follicular T helper cell differentiation and robust antibody responses, and cyclic di-AMP, a vita-PAMP produced by live Gram-positive bacteria that engages the STING pathway to trigger endoplasmic reticulum stress, reticulophagy, and type I interferon production. These data mechanistically explain the superiority of live vaccines in generating immunity and lay the groundwork for the development of vita-PAMP adjuvants to safely mimic live vaccines and achieve long-lasting protective immunity with killed or subunit vaccines.

More recently, we have defined non-canonical functions of inflammatory caspases in tissue homeostasis. The shortest isoform of human CASP5 (CASP5c) is enriched in intestinal epithelial transit-amplifying cells, where it amplifies Wnt signaling through cleavage of APC, thereby promoting epithelial proliferation and regeneration. Because this pathway is activated in patients with inflammatory bowel disease and inactivated in colorectal cancer, our data reveal a novel and direct link between innate immune proteases and epithelial integrity. Meanwhile, we have identified another novel non-canonical role for the inflammasome within the bone marrow stroma, which acts as a critical barrier against Myc-driven lymphomagenesis. This finding highlights innate immune mechanisms that suppress early oncogenic events.

Together, our discoveries reveal one integral picture of the innate immune system's continuous interrogation of the context of cell death and microbial viability, deciding on inflammation versus tolerance and repair versus anti-tumor surveillance. The Blander Lab studies the molecular logic underlying these decisions at the phagosome, the inflammasome, and the regulated cell death pathways, with the hope that mechanistic understanding will be translated into better vaccines, strategies to promote mucosal healing, and cancer immunoprevention.