Until recently, CREM signaling was considered inhibitory to T cells because many T cell-relevant target genes are transcriptionally repressed by CREM or ICER (Table 1) [35]. In human T cells, the expression of both CREMα and ICER is inducible following TCR activation or calcium mobilization [32,36–38]. A growing body of literature suggests that CREMα is involved in the antithetic regulation of the cytokine genes IL17A and IL2 in both health and disease (Figure 2 and Box 2). meCpG mediates tissue-specific silencing of CREMα, which may affect T lymphocyte differentiation [34]. Naïve CD45RA+CCR7+CD4+ and CD45R0+CCR7+CD4+ ‘central memory’ T lymphocytes share subset-specific homing to secondary lymphatic tissues and have gene expression patterns that are partially similar. Naïve and central memory CD4+ T cells express high levels of IL-2, but relatively low amounts of IL-17A in response to TCR stimulation. By contrast, CD45R0+CCR7−CD4+ ‘effector memory’ T lymphocytes are primarily detected in the peripheral blood, express perforin and effector cytokines (including IFN-γ, IL-4, and IL-17A) in response to TCR stimulation, but fail to produce IL-2 [34,39]. Recently, tissue-specific CREMα expression patterns have been documented
