Transcriptional profiles reveal a stepwise developmental program of memory CD8+ T cell differentiation. Issue 7 (11th February 2015) - Roychoudhuri, Rahul
Highlights: We perform whole transcriptome analysis of distinct CD8 + T-cell memory populations arising endogenously following immunization with clinical and pre-clinical vaccines regimens. We find that transcriptional proximity relationships between endogenous T N, T CM, T EM and T EFF place memory cells at an intermediate state of differentiation between T N and T EFF . We compare transcriptional differences between T N, T CM, T EM and T EFF cells with known changes when CD8 + T cells undergo repeated antigen stimulation. We find that at a single time-point following vaccination, cells can be found with the transcriptional imprint of distinct exposures to antigen. Our analysis favors the progressive differentiation model whereby cumulative antigen stimulation drives differentiation specifically from T N > T CM > T EM > T EFF . Abstract: The generation of CD8 + T-cell memory is a major aim of vaccination. While distinct subsets of CD8 + T-cells are generated following immunization that differ in their ability to confer long-term immunity against infection, the transcriptional profiles of these subsets within endogenous vaccine-induced CD8 + T cell responses have not been resolved. Here, we measure global transcriptional profiles of endogenous effector ( T EFF ), effector memory ( T EM ) and central memory ( T CM ) CD8 + T-cells arising from immunization with three distinct prime-boost vaccine regimens. While a proportion of transcripts were uniquely regulated within distinct CD8 + T cell populations, we observed progressive up- or down-regulation in the expression of a majority of differentially expressed transcripts when subsets were compared in the order T N > T CM > T EM > T EFF. Strikingly, when we compared global differences in gene expression between T N, T CM, T EM and T EFF cells with known transcriptional changes that result when CD8 + T cells repetitively encounter antigen, our analysis overwhelmingly favored a model whereby cumulative antigen stimulation drives differentiation specifically from T N > T CM > T EM > T EFF and this was common to all vaccines tested. These findings provide insight into the molecular basis of immunological memory and identify potential biomarkers for characterization of vaccine-induced responses and prediction of vaccine efficacy.