Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells

Abstract

The only cells of the hematopoietic system that undergo self-renewal for the lifetime of the organism are long-term hematopoietic stem cells and memory T and B cells. To determine whether there is a shared transcriptional program among these self-renewing populations, we first compared the gene-expression profiles of naïve, effector and memory CD8(+) T cells with those of long-term hematopoietic stem cells, short-term hematopoietic stem cells, and lineage-committed progenitors. Transcripts augmented in memory CD8(+) T cells relative to naïve and effector T cells were selectively enriched in long-term hematopoietic stem cells and were progressively lost in their short-term and lineage-committed counterparts. Furthermore, transcripts selectively decreased in memory CD8(+) T cells were selectively down-regulated in long-term hematopoietic stem cells and progressively increased with differentiation. To confirm that this pattern was a general property of immunologic memory, we turned to independently generated gene expression profiles of memory, naïve, germinal center, and plasma B cells. Once again, memory-enriched and -depleted transcripts were also appropriately augmented and diminished in long-term hematopoietic stem cells, and their expression correlated with progressive loss of self-renewal function. Thus, there appears to be a common signature of both up- and down-regulated transcripts shared between memory T cells, memory B cells, and long-term hematopoietic stem cells. This signature was not consistently enriched in neural or embryonic stem cell populations and, therefore, appears to be restricted to the hematopoeitic system. These observations provide evidence that the shared phenotype of self-renewal in the hematopoietic system is linked at the molecular level.

Fig. 1.

Memory CD8⁺ T cell-enriched transcripts are also enriched in Lt-HSC, whereas memory CD8⁺ T cell-depleted transcripts are also depleted in Lt-HSC. Volcano plots comparing the relative gene expression in the two cell populations listed above each plot are shown. For memory-enriched transcripts, all 12,422 transcripts on the MgU74v2 A chip are shown for the memory vs. naïve comparison (A). Transcripts whose expression was relatively enriched in memory cells (unlogged fold change ≥1.4) are shown in green and were used for subsequent analysis. This criterion was based on within-replicate analyses providing empirical estimation of experimental noise. (B) Relative expression in the memory vs. effector cell comparison for those transcripts selected in A. Transcripts whose fold change is ≥1.4 are shown in blue and were used for subsequent analysis. The transcripts meeting criteria in both A and B were then plotted for their relative expression in C as Lt-HSC vs. LCP, Lt-HSC vs. St-HSC, and St-HSC vs. LCP comparisons. In each case, the number of transcripts whose log₂ (fold change) is greater or less than zero is shown at the top of the plot. Those transcripts whose expression in Lt-HSC vs. LCP was >1.4 were then highlighted in red in D. In each case, the numbers of red transcripts whose log₂ (fold change) is greater or less than zero is shown at the bottom of the plot. For memory-depleted transcripts, the 98 transcripts whose expression was relatively depleted (fold change of ≤1.4) in memory T cells relative to naïve (E) and effector (F) T cells are plotted for their relative expression in Lt-HSC vs. LCP, Lt-HSC vs. St-HSC, and St-HSC vs. LCP (G). The number of transcripts whose log₂ (fold change) is greater or less than zero is shown at the top of the plot. Those transcripts whose expression in Lt-HSC vs. LCP was <−1.4 were then highlighted in red (H), and their number greater or less than zero is shown at the bottom of the plot.

Fig. 2.

Memory B cell-enriched transcripts are also enriched in Lt-HSC, whereas memory B cell-depleted transcripts are also depleted in Lt-HSC. The 272 transcripts whose expression was relatively enriched (fold change ≥1.4) in memory B cells relative to naïve (A), germinal center (B), and plasma B cells (C) are plotted for their relative expression in Lt-HSC vs. LCP, Lt-HSC vs. St-HSC, and St-HSC vs. LCP (D). The number of transcripts whose log₂ (fold change) is greater or less than zero is shown at the top of the plot. Those transcripts whose expression in Lt-HSC vs. LCP was >1.4 were then highlighted in red (E), and their number greater or less than zero is shown at the bottom of the plot. The 481 transcipts whose expression was relatively depleted (≤−1.4) in memory B cells relative to naïve (F), germinal center (G), and plasma B cells (H) are plotted for their relative expression in Lt-HSC vs. LCP, Lt-HSC vs. St-HSC, and St-HSC vs. LCP (I). The number of transcripts whose log₂ (fold change) is greater or less than zero is shown at the top of the plot. Those transcripts whose expression in Lt-HSC vs. LCP was <−1.4 were then highlighted in red (J), and their number greater or less than zero is shown at the bottom of the plot.

Fig. 3.

Coordinately regulated transcripts in both memory CD8⁺ T cells and memory B cells are also coordinately regulated in Lt-HSC. (A) Those transcripts whose expression in coordinately regulated in memory B cells and memory T cells are listed. (B) Enriched transcripts are plotted for their relative expression in Lt-HSC vs. LCP, Lt-HSC vs. St-HSC, and St-HSC vs. LCP. (C) Depleted transcripts are plotted for their relative expression in Lt-HSC vs. LCP, Lt-HSC vs. St-HSC, and St-HSC vs. LCP. The number of transcripts whose log₂ (fold change) is greater or less than zero is shown at the top of the plots.

Fig. 4.

Coordinately regulated transcripts in memory B and memory T cells are coordinately regulated in several different data sets of hematopoietic stem cells but are not coordinately regulated in neural or ES cells. Transcripts listed in Fig. 5 are on the y axis, and their expression is plotted as a heat map in each of the comparisons listed on the x axis. Up-regulated transcripts are shown in red, and down-regulated transcripts are shown in green. LiLt and LiSt represent Lt-HSC and St-HSc in the published data of Akashi et al. (28) HSC and BM represent the Lt-HSC and mature bone marrow of Ramalho-Santos et al. (27). FlH and FlL represent the fetal liver HSC and lineage committed progenitors of Ivanova et al. (14). NSC and LVB represent the neural stem cells and lateral ventrical of the brain of Ramalho-Santos et al. (27) iNSC represent the neural stem cells of Ivanova et al. (14). ESC and BM represent the ES cells and bone marrow of Ramalho-Santos et al. (27) iESC and Mbc represent the ES cells and mature bone marrow of Ivanova et al. (14). All of the data sets were pooled together for rma analysis as described in Methods.