T Cell Receptor and Cytokine Signaling Can Function at Different Stages to Establish and Maintain Transcriptional Memory and Enable T Helper Cell Differentiation

Abstract

Experienced T cells exhibit immunological memory via a rapid recall response, responding to restimulation much faster than naïve T cells. The formation of immunological memory starts during an initial slow response, when naïve T cells become transformed to proliferating T blast cells, and inducible immune response genes are reprogrammed as active chromatin domains. We demonstrated that these active domains are supported by thousands of priming elements which cooperate with inducible transcriptional enhancers to enable efficient responses to stimuli. At the conclusion of this response, a small proportion of these cells return to the quiescent state as long-term memory T cells. We proposed that priming elements can be established in a hit-and-run process dependent on the inducible factor AP-1, but then maintained by the constitutive factors RUNX1 and ETS-1. This priming mechanism may also function to render genes receptive to additional differentiation-inducing factors such as GATA3 and TBX21 that are encountered under polarizing conditions. The proliferation of recently activated T cells and the maintenance of immunological memory in quiescent memory T cells are also dependent on various cytokine signaling pathways upstream of AP-1. We suggest that immunological memory is established by T cell receptor signaling, but maintained by cytokine signaling.

IL‐2/IL‐7‐inducible factors pioneer the path to T cell differentiation in advance of lineage‐defining factors

“…For example, the intensively studied Th2 LCR within the Rad50 locus comprises seven distinct DHSs in Th2 cells where it controls activation of the Th2-specific IL-4, IL-13, and IL-5 genes (Fields et al, 2004). This locus is epigenetically reprogrammed and primed with active histone modifications within 24-48 h of activation of TCR signaling when T N cells transform into T B cells (Bevington et al, 2016(Bevington et al, , 2017b. However, just two of these DHSs are initially opened up as epigenetically primed DHSs when Th0 cells are first activated (Bevington et al, 2016(Bevington et al, , 2017b.…”

“…The IL-2 dependence at pDHSs was exemplified by multiple regions that we previously identified as primed in recently activated T-blast cells (Bevington et al, 2016), including the Th2-specific LCR (Fields et al, 2004) within the Rad50 gene (Fig 2E), which regulates an archetypal Th2-specific cytokine gene cluster that includes Il4, Il13, and Il5 (Bevington et al, 2017b), the Tnfsr9 locus, and the IL-2regulated Cish locus region (Li et al, 2017). For these loci, IL-2 pDHSs were present in CD4 T B IL-2 and CD4 T B DMSO cells, and they were reduced upon IL-2 removal and by Ruxolitinib treatment.…”

TlR2 and TlR4 are involved in the treatment of rheumatoid arthritis synovial fibroblasts with a medicated serum of asarinin through inhibition of Th1/Th17 cytokines

“…IFN-γ, IL-6, TNF-α and IL-17A are inflammatory cytokines and IFN-γ and TNF-α are T h 1-type cytokines (6). IL-6 is also the main inflammatory factor in RA joint inflammation, but its pathogenic effect is different from that of IL-1 and TNF-α, which mainly induces the production of immunoglobulins and the formation of acute phase proteins (37)(38)(39)(40). Although T h 2 cells secrete IL-6, IL-6 still serves a role as an inflammatory cytokine.…”

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

“…Memory CD4 T‐cells retain characteristics of the activated CD4 T‐cells from which they are derived and can, therefore, also be divided based on their functional responses 4, 5. This cellular memory is thought to be retained by epigenetic changes to the cell's DNA or associated histone proteins that keep genes in an open or closed state depending on their expression during the primary immune response 3, 6, 7. Many genes are thought to be maintained in a poised state in memory T‐cells, enabling rapid re‐expression of effector molecules following T‐cell reactivation by antigen‐presenting cells (APCs).…”