3D chromatin reprogramming primes human memory T _H 2 cells for rapid recall and pathogenic dysfunction

Abstract

Memory T cells provide long-lasting defense responses through their ability to rapidly reactivate, but how they efficiently “recall” an inflammatory transcriptional program remains unclear. Here, we show that human CD4 + memory T helper 2 (T H 2) cells carry a chromatin landscape synergistically reprogrammed at both one-dimensional (1D) and 3D levels to accommodate recall responses, which is absent in naive T cells. In memory T H 2 cells, recall genes were epigenetically primed through the maintenance of transcription-permissive chromatin at distal (super)enhancers organized in long-range 3D chromatin hubs. Precise transcriptional control of key recall genes occurred inside dedicated topologically associating domains (“memory TADs”), in which activation-associated promoter-enhancer interactions were preformed and exploited by AP-1 transcription factors to promote rapid transcriptional induction. Resting memory T H 2 cells from patients with asthma showed premature activation of primed recall circuits, linking aberrant transcriptional control of recall responses to chronic inflammation. Together, our results implicate stable multiscale reprogramming of chromatin organization as a key mechanism underlying immunological memory and dysfunction in T cells.

Active maintenance of CD8+ T cell naivety through regulation of global genome architecture

“…TFs, such as TCF-1 and AP1 factors, contribute to chromatin spatial organization in central memory CD8 + T cells, with TCF1 ablation resulting in an inability to engage transcription of genes required for secondary expansion and metabolic reprogramming. 51 , 52 These observations imply that genome architecture is not sufficient to instruct cell-type-specific gene transcription, but rather, TFs serve to preconfigure the spatial organization of chromatin to transcriptionally poise appropriate genes for rapid activation following secondary challenge. Hence, the unique chromatin landscapes formed within naive and effector/memory CD8 + T cells form an important scaffold that is read by specific TFs indicating their role in determining line-age-specific differentiation.…”

Antigen exposure reshapes chromatin architecture in central memory CD8+T cells and imprints enhanced recall capacity

“…Our efforts in this direction were impeded by the paucity of murine T CM cells and further diminished numbers of viable cells after 24-h ex vivo stimulation. However, a most recent study comprehensively mapped 3D genome organization in human naive CD4 + and memory T H 2 cells at resting state and after 24-h ex vivo TCR stimulation, demonstrating extensive changes in compartment scores, TAD organization, and ChrInt loop strength between naive and memory T cells ( 47 ). Significantly, a sizable fraction of the memory-specific TADs and chromatin loops was linked to recall-induced genes, such as MAF and IL9 ( 47 ).…”

“…However, a most recent study comprehensively mapped 3D genome organization in human naive CD4 + and memory T H 2 cells at resting state and after 24-h ex vivo TCR stimulation, demonstrating extensive changes in compartment scores, TAD organization, and ChrInt loop strength between naive and memory T cells ( 47 ). Significantly, a sizable fraction of the memory-specific TADs and chromatin loops was linked to recall-induced genes, such as MAF and IL9 ( 47 ). Collectively, these advances strongly support the notion that the reprogrammed 3D genome topology in memory CD4 + and CD8 + T cells creates permissive chromatin environment to facilitate rapid transcriptional induction in response to recall stimulation by their cognate antigens.…”

HIV Expression in Infected T Cell Clones

“…Both phenotypic maintenance and interconversion are driven by antigen and cytokine environments and manifested through engagement of cell surface receptors and downstream signaling cascades, culminating in institution of specialized, phenotype-specific transcriptional programs and chromatin structural changes [ 192 ]. There are numerous examples of how effector cell lineage fidelity and memory cell readiness for secondary immune response are durably altered through epigenetic changes [ 193 , 194 , 195 , 196 , 197 , 198 , 199 ], and here we relate both a general mechanism and a specific example of how such signal transduction can activate expression of select CD4+ T cell effector genes, either immediately through engagement of proximal enhancers or super-enhancers or more durably by altering chromatin structure ( Figure 3 ) [ 200 ]. Notably, CD4+ T cell phenotypes, including capacity for antigen-driven clonal expansion, are regulated by many of the same factors and mechanisms shown to modulate HIV-1 gene expression, as described in previous sections of this review (e.g., SP1, AP-1, BATF, NF-κB, NFAT, and IRF4).…”