Abstract
Streptococcus pneumoniae is an encapsulated bacterium that causes significant global morbidity and mortality. The nasopharynxes of children are believed to be the natural reservoir of pneumococcus and by adulthood nasopharyngeal carriage is infrequent; such infrequency may be due to demonstrable pneumococcal specific T and B-cell responses. HLA Class 2 tetrameric complexes have been used to characterise antigen specific T-cell responses in a variety of models of infection. We therefore sought to determine the frequency and phenotype of pneumococcal specific T-cells, using a novel HLA-DRB1*1501 tetramer complex incorporating a recently defined T-cell epitope derived from the conserved pneumococcal serine/threonine kinase (StkP). We were able to detect direct ex-vivo StkP446–60-tetramer binding in HLA-DRB1*1501 adults. These StkP446–60-tetramer binding T-cells had increased CD38 expression and were enriched in CCR7- CD45RA+ expression indicating recent and on-going activation and differentiation. Furthermore, these StkP446–60-tetramer binding T-cells demonstrated rapid effector function by secreting interferon-gamma on stimulation with recombinant StkP. This is the first study to directly enumerate and characterise pneumococcal specific T-cells using HLA class 2 tetrameric complexes. We found that ex-vivo pneumococcal-specific T cells were detectable in healthy adults and that they were enriched with cell surface markers associated with recent antigen exposure and later stages of antigen-driven differentiation. It is likely that these activated pneumococcal specific T-cells reflect recent immunostimulatory pneumococcal exposure in the nasopharynx and it is possible that they may be preventing subsequent colonisation and disease.
Highlights
Streptococcus _neumonia is an extracellular bacterium that causes significant mortality and morbidity globally [1]
Identifying pneumococcal specific T-cells Peripheral blood mononuclear cells (PBMCs) and derived T-cell clones and lines were derived from 10 healthy volunteers (HV1-10), all of whom expressed HLADRB1501
The HLA-DRB1*1501-StkP tetramer was able to bind to a pneumococcal specific IFN-gamma secreting T cell clone from HV1; this clone had been generated by its ability to secrete IFN-gamma in response to the StkP HLA-DRB1*1501 restricted epitope QSFQISNYVGRKSSD (StkP446–60)
Summary
Streptococcus _neumonia (pneumococcus) is an extracellular bacterium that causes significant mortality and morbidity globally [1]. Young children are often nasally colonised and have the highest incidence of pneumococcal infections. Anti-pneumococcal protein antibody responses are T-cell dependant [10] and T-cell responses, as expected, are detectable in adults and children to both whole pneumococcus and pneumococcal proteins and peptides; these have been demonstrated by measuring Tcell proliferation and cytokine secretion [6,7,8]. It is likely that these responses are important in clearing mucosal colonisation in children and maintaining protective immunity in adults [11,12]. Young adults are rarely colonised with pneumococcus and have a relatively low incidence of pneumococcal infection. We found that pneumococcal specific T-cells were detectable in most healthy adults These T-cells have increased expression of CD38, suggesting that they have been recently activated
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