Abstract
BackgroundMultiparameter flow cytometry has revealed extensive phenotypic and functional heterogeneity of CD4 T cell responses in mice and humans, emphasizing the importance of assessing multiple aspects of the immune response in correlation with infection or vaccination outcome. The aim of this study was to establish and validate reliable and feasible flow cytometry assays, which will allow us to characterize CD4 T cell population in humans in field studies more fully.Methodology/Principal FindingsWe developed polychromatic flow cytometry antibody panels for immunophenotyping the major CD4 T cell subsets as well as broadly characterizing the functional profiles of the CD4 T cells in peripheral blood. We then validated these assays by conducting a pilot study comparing CD4 T cell responses in distinct populations of healthy adults living in either rural or urban Kenya. This study revealed that the expression profile of CD4 T cell activation and memory markers differed significantly between African and European donors but was similar amongst African individuals from either rural or urban areas. Adults from rural Kenya had, however, higher frequencies and greater polyfunctionality among cytokine producing CD4 T cells compared to both urban populations, particularly for “Th1” type of response. Finally, endemic exposure to malaria in rural Kenya may have influenced the expansion of few discrete CD4 T cell populations with specific functional signatures.Conclusion/SignificanceThese findings suggest that environmentally driven T cell activation does not drive the dysfunction of CD4 T cells but is rather associated with greater magnitude and quality of CD4 T cell response, indicating that the level or type of microbial exposure and antigenic experience may influence and shape the functionality of CD4 T cell compartment. Our data confirm that it is possible and mandatory to assess multiple functional attributes of CD4 T cell response in the context of infection.
Highlights
CD4 T cells are a central component of the immune response to a wide variety of pathogens
We found no evidence of ‘‘exhausted’’ CD4 T cells based on our panel of cell surface markers, more detailed and larger studies of P. falciparum-specific CD4 T cells in immune adults and children presenting with different severity of manifestations of malaria infection are required to analyse how endemic exposure and/or infection by P. falciparum may impact on the phenotypic characteristics of CD4 T cell compartment, including PD-1 and other markers [24,45]
Our observations indicate that environmentally triggered T cell stimulation in rural Kenya leads to higher magnitude of cytokine response as well as an increase in multifunctional cells within the total CD4 T cell pool, while the presence of a dominant single cytokine producing CD4 T cell population seems associated with differential Ag experience in urban Kenya
Summary
CD4 T cells are a central component of the immune response to a wide variety of pathogens. Recent studies of Ag-specific T cell responses to vaccines, or after certain infections (reviewed in [13,14]), have revealed an enormous phenotypic heterogeneity and functional diversity within the CD4 T cell population, emphasizing the importance of the quality (i.e. the combination of different functions at a single cell or cell population level) of a T cell response, as opposed to its simple magnitude or response of a single population, in correlation with clinical outcome. The aim of this study was to establish and validate reliable and feasible flow cytometry assays, which will allow us to characterize CD4 T cell population in humans in field studies more fully
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