A New Understanding Of How Immune System Targets Disease

Recognizing molecules as "self," versus foreign invaders to bedestroyed, is a central responsibility of the immune system. Tumorsclosely resemble self or "host" tissues and can confuse the system.Viruses and bacteria are immediately recognizable as foreign, but havelearned to change shape so often that the system loses track of them.Pathogens use the same tricks to escape the immunity provided byvaccines.

In an effort to deny diseases the ability to hide, researchershave for years been asking a key question: Why do our bodies selectcertain, small pieces (epitopes) of each disease-causing molecule totrigger an immune response, while ignoring the rest? Those few,triggering protein fragments are termed "immunodominant."Unfortunately, the immune system sometimes makes poor choices aboutwhich epitopes to pay attention to, and which to ignore. Understandingof how immunodominance is conferred would enable vaccine designers toshift the immune system spotlight to parts of pathogens that theycannot change in efforts to escape detection. For example, a vaccinecould be designed to target a protein fragment central to a virus'sability to reproduce, or to invade its prey.

"Our study identified for the first time the chemical mechanismthat determines immunodominance, and proved that it can be fine-tuned,"said Andrea Sant, Ph.D., a professor within the David H. Smith Centerfor Vaccine Biology and Immunology at the University of RochesterMedical Center, and the study's lead author. "If confirmed, thefindings could launch a new wing of research seeking to re-engineerviruses, bacteria and tumor cells to make them hundreds of times morelikely to be noticed and destroyed by our immune system."

Study Details

As part of the immune response, Tcells, one type of white blood cell, partner with dendritic cells tomake careful decisions about which pieces of pathogens will trigger afull-scale immune attack. Dendritic cells roam the body, checking eachparticle they come across for a self or invader "label." Uponencountering an invader, a dendritic cell will "swallow it," cut it up,and carry the pieces to the nearest lymph node.

Once in the lymph node, major histocompatibility complex (Mhc)proteins inside the dendritic cell present immunodominant epitopes onthe cell's surface for consideration by T cells gathered there. Onceactivated by high enough levels of target epitope for long enoughperiods of time, T cells become armed and capable of destroying thepathogen in question.

Sant's study provides the first proof that it is somethingabout the invader epitope itself that drives and focuses T cellresponse, and not some action of enzymes inside the dendritic cell asonce thought. The quality determining immunodominance is the strengthand lifespan (kinetic stability) of the bond between the Mhc proteinand a given epitope. Kinetic stability determines whether, in the faceof competing reactions within the immune system, an epitope:Mhc complexcan remain intact on the dendritic cell surface long enough to demand Tcell attention. Sant's team found that immunodominant peptides werelikely to stay bound to Mhc molecules for an average of 150 hours,where nondominant epitopes held on for less than 10 hours.

"What's exciting is that kinetic stability is determined by howtightly an epitope fits into the Mhc protein, and we can control thatfit with standard techniques," Sant said. "By switching out singleamino acid building blocks, we were able to drastically increase thepotency of the T cell response to target epitopes. If confirmed, thisdiscovery will bring immundominance and a major portion of the immunesystem under our control for the first time."