Functional and phenotypic characterization of tetanus toxoid-specific human CD4+ T cells following re-immunization

The formation of immunological memory is a hallmark of adaptive immunity and the goal of vaccination. For CD8(+) T cells, successful generation of memory cells has been linked to IL-7 receptor alpha (IL-7R alpha) expression, suggesting a role for IL-7 signaling, which in turn is important for preventing T cell apoptosis. We thus investigated the kinetics and changes of IL-7R alpha and anti-apoptotic protein Bcl-2 expression levels in tetanus toxoid (TT) -specific CD4(+) T cells at different time points prior and after TT reimmunization of TT-immune individuals. Prior to re-immunization, most TT-specific CD4(+) T cells were high IL-2 producers, CD45RA(-)CCR7(+), IL-7R alpha(high)Bcl-2(high) cells, resembling typical long-lived central memory cells. Already 5 days, and more importantly at the peak of the response, after TT re-immunization, a substantial fraction of these cells secreted also IFN-gamma, down-regulated CCR7, IL-7R alpha and Bcl-2 and became Ki67 positive, resembling effector memory cells. In contrast, TT-specific CD4(+) T cells found 60 days or later after re-immunization were again as baseline. Interestingly, a significant fraction of IL-7R alpha(high) Bcl-2(high) TT-specific CD4(+) T cells, i.e. the proposed memory cell precursors, remained stable at any time point upon reimmunization. Together, these results suggest that IL-7R alpha expression levels might be a useful marker for identifying long-lived Ag-specific CD4(+) T cells in memory T cells.