Usually, the T cells of the immune system respond to a specific characteristic (antigen) of a microbe, thus generating protective immunity. As reported in the journal Immunity, an international team of scientists discovered an exception to this rule. That is, a group of divergent bacterial pathogens, including pneumococci, all share a small, highly conserved protein sequence, which is conservedly presented and recognized by human T cells throughout the population.
The study set out to understand the immune mechanisms that protect against pneumococcus, a bacterial pathobiont that can reside harmlessly in the mucosa of the upper respiratory tract, but can also cause infectious diseases, especially in infants and older adults, ranging from infections from the middle ear and paranasal sinuses to pneumococcal infections. pneumonia and invasive bloodstream infections.
Most of the pneumococcal polysaccharide conjugate (PCV) vaccines currently in use are effective against 10-13 serotypes, but increasing serotype replacement is becoming a problem.
The WHO estimates that each year 1.6 million people die from pneumococcal disease, including between 0.7 and 1 million children under 5 years of age, most of whom live in developing countries.
The study co-led by the Monash Biomedicine Discovery Institute, in collaboration with the National Institute for Public Health and the Environment (RIVM) and Utrecht University in the Netherlands and Cardiff University in the UK, identified a crucial fragment of the pneumococcal toxin pneumolysin that was commonly presented by a particular class of human antigen-presenting molecules and recognized by the T cells of most people who naturally develop specific immunity to pneumococcal proteins.
The study further discovered that the uniformly presented and widely recognized bacterial protein fragment was not unique to pneumococcal pneumolysin, but was shared by a large family of bacteria called cholesterol-dependent cytolysins (CDCs). These are produced by divergent bacterial pathogens that primarily affect humans and cause a variety of respiratory, gastrointestinal, or vaginal infectious diseases.
First author Dr. Lisa Ciacchi said, “Use of the national synchrotron was key in providing molecular insights into how T-cell receptors view these conserved antigens when presented by common human leukocyte antigen (HLA) molecules.”
Shared first author Dr. Martijn van de Garde said: “We have not yet identified the exact role of nearly ubiquitous T cell populations in this conserved protein fragment that is commonly present during ongoing colonizations or infections with CDC-producing bacteria. Whether the T cells have a cross-protective mode of action or have a tolerant anti-inflammatory function remains to be investigated.”
Shared first author Dr. Kristin Ladell said: “The identification of T cells that recognize a ubiquitous bacterial motif using T cell receptors that are shared among HLA-prevalent individuals is very exciting. The reagents generated for this study are now being they can use to study groups of patients to examine how common these shared TCRs are and how they relate to immune protection.”
Continued research could inform the development of interventions for people to more efficiently resist or eliminate CDC-related bacterial diseases.
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