It feels like lupus: accessible science for the low-vision community on immune system dysfunction in lupus.

Science communication is often confined to spoken, written or graphical form, neglecting the integration of other tools that would open inclusive scientific dialog to the low-vision community. To address this barrier, members from the Monash Rheumatology clinical and laboratory research groups formed a Lupus Sensory Science team to create a breakout room at the 2023 Monash Sensory Science Exhibit on Autoimmunity. Our goal was to develop multimodal displays and artworks to engage participants with blindness and low vision with the immunological underpinnings of systemic lupus erythematosus (SLE). Here I describe how we created several stations using a combination of tactile posters and models to communicate disease manifestations and immune system dysregulation in SLE. I reflect on how participants keenly engaged with our artworks, asking thoughtful questions that stimulated interesting discussions about treatment options in SLE. In addition, I analyze how our exhibit could be improved to further increase accessibility for the low-vision community. Overall, we learned a lot about how to be inclusive in scientific communication methods and we will strive to continue to engage all members of our community in scientific discussion.

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

The differentiation of naive CD8+ T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8+ T cells. We observe that the architecture of the naive CD8+ T cell genome is distinct from effector and memory genome configurations, with extensive changes within discrete functional chromatin domains associated with effector/memory differentiation. Deletion of BACH2, or to a lesser extent, reducing SATB1 DNA binding, within naive CD8+ T cells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8+ T cells act to restrain T cell differentiation by actively enforcing a unique naive chromatin state.

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

The differentiation of naïve CD8+ cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naïve, effector and memory virus-specific CD8+ T cells. We observed that the architecture of the naive CD8+ T cell genome was distinct from effector and memory genome configurations with extensive changes within discrete functional chromatin domains. However, deletion of the BACH2 or SATB1 transcription factors was sufficient to remodel the naïve chromatin architecture and engage transcriptional programs characteristic of differentiated cells. This suggests that the chromatin architecture within naïve CD8+ T cells is preconfigured to undergo autonomous remodelling upon activation, with key transcription factors restraining differentiation by actively enforcing the unique naïve chromatin state.

Type 1 interferon suppresses expression and glucocorticoid induction of glucocorticoid-induced leucine zipper (GILZ).

SLE is a systemic multi-organ autoimmune condition associated with reduced life expectancy and quality of life. Glucocorticoids (GC) are heavily relied on for SLE treatment but are associated with detrimental metabolic effects. Type 1 interferons (IFN) are central to SLE pathogenesis and may confer GC insensitivity. Glucocorticoid-induced leucine zipper (GILZ) mediates many effects of GC relevant to SLE pathogenesis, but the effect of IFN on GC regulation of GILZ is unknown. We performed in vitro experiments using human PBMC to examine the effect of IFN on GILZ expression. JAK inhibitors tofacitinib and tosylate salt were used in vivo and in vitro respectively to investigate JAK-STAT pathway dependence of our observations. ChiP was performed to examine glucocorticoid receptor (GR) binding at the GILZ locus. Several public data sets were mined for correlating clinical data. High IFN was associated with suppressed GILZ and reduced GILZ relevant to GC exposure in a large SLE population. IFN directly reduced GILZ expression and suppressed the induction of GILZ by GC in vitro in human leukocytes. IFN actions on GILZ expression were dependent on the JAK1/Tyk2 pathway, as evidenced by loss of the inhibitory effect of IFN on GILZ in the presence of JAK inhibitors. Activation of this pathway led to reduced GR binding in key regulatory regions of the GILZ locus. IFN directly suppresses GILZ expression and GILZ upregulation by GC, indicating a potential mechanism for IFN-induced GC resistance. This work has important implications for the ongoing development of targeted GC-sparing therapeutics in SLE.

GILZ regulates type I interferon release and sequesters STAT1.

Glucocorticoids remain a mainstay of modern medicine due to their ability to broadly suppress immune activation. However, they cause severe adverse effects that warrant urgent development of a safer alternative. The glucocorticoid-induced leucine zipper (GILZ) gene, TSC22D3, is one of the most highly upregulated genes in response to glucocorticoid treatment, and reduced GILZ mRNA and protein levels are associated with increased severity of inflammation in systemic lupus erythematosus (SLE), Ulcerative Colitis, Psoriasis, and other autoimmune/autoinflammatory diseases. Here, we demonstrate that low GILZ permits expression of a type I interferon (IFN) signature, which is exacerbated in response to TLR7 and TLR9 stimulation. Conversely, overexpression of GILZ prevents IFN-stimulated gene (ISG) up-regulation in response to IFNα. Moreover, GILZ directly binds STAT1 and prevents its nuclear translocation, thereby negatively regulating IFN-induced gene expression and the auto-amplification loop of the IFN response. Thus, GILZ powerfully regulates both the expression and action of type I IFN, suggesting restoration of GILZ as an attractive therapeutic strategy for reducing reliance on glucocorticoids.

CD8+ T-Cell Memory: The Why, the When, and the How.

The generation of effective adaptive T-cell memory is a cardinal feature of the adaptive immune system. The establishment of protective T-cell immunity requires the differentiation of CD8+ T cells from a naive state to one where pathogen-specific memory CD8+ T cells are capable of responding to a secondary infection more rapidly and robustly without the need for further differentiation. The study of factors that determine the fate of activated CD8+ T cells into either effector or memory subsets has a long history. The advent of new technologies is now providing new insights into how epigenetic regulation not only impacts acquisition and maintenance of effector function, but also the maintenance of the quiescent yet primed memory state. There is growing appreciation that rather than distinct subsets, memory T-cell populations may reflect different points on a spectrum between the starting naive T-cell population and a terminally differentiated effector CD8+ T-cell population. Interestingly, there is growing evidence that the molecular mechanisms that underpin the rapid effector function of memory T cells are also observed in innate immune cells such as macrophages and natural killer (NK) cells. This raises an interesting hypothesis that the memory/effector T-cell state represents a default innate-like response to antigen recognition, and that it is the naive state that is the defining feature of adaptive immunity. These issues are discussed.

Running to Stand Still: Naive CD8+ T Cells Actively Maintain a Program of Quiescence.

CD8+ T cells play a pivotal role in clearing intracellular pathogens and combatting tumours. Upon infection, naïve CD8+ T cells differentiate into effector and memory cells, and this program is underscored by large-scale and coordinated changes in the chromatin architecture and gene expression. Importantly, recent evidence demonstrates that the epigenetic mechanisms that regulate the capacity for rapid effector function of memory T cells are shared by innate immune cells such as natural killer (NK) cells. Thus, it appears that the crucial difference between innate and adaptive immunity is the presence of the naïve state. This important distinction raises an intriguing new hypothesis, that the naïve state was evolutionary installed to restrain a default program of effector and memory differentiation in response to antigen recognition. We argue that the hallmark of adaptive T immunity is therefore the naïve program, which actively maintains CD8+ T cell quiescence until receipt of appropriate activation signals. In this review, we examine the mechanistic control of naïve CD8+ T cell quiescence and summarise the multiple levels of restraint imposed in naïve cells in to limit spontaneous and inappropriate activation. This includes epigenetic mechanisms and transcription factor (TF) regulation of gene expression, in addition to novel inhibitory receptors, abundance of RNA, and protein degradation.