Biology subjects

Travis, M. A.

Publications and source records attributed to Travis, M. A..

3 recordsLinked to original sources

bioRxiv2025

Inflammatory responses following CRISPR modification of the nuclear localisation sequence in endogenous interleukin-1α

Interleukin (IL)-1 is a pro-inflammatory member of the IL-1 cytokine superfamily and is important for inflammatory responses to infection and injury. Unlike pro-IL-1{beta}, pro-IL-1 is mainly localised to the nucleus upon expression. This is mediated by a nuclear localisation sequence (NLS) responsible for its importin-dependent transport into the nucleus. This nuclear localisation and the presence of histone acetyl transferase (HAT)-binding domains within the pro-domain suggest a role of this cytokine in gene transcription regulation. In addition, nuclear trafficking of pro-IL-1 is proposed to regulate its secretion. To-date, studies on the nuclear role of pro-IL-1 have used overexpression systems. Here, we generated a mouse where the endogenous Il1a gene was edited with CRISPR to disrupt the NLS (mNLS). Using an in vitro approach with murine macrophages we found that this NLS mutation did not affect pro-IL-1 RNA expression levels in response to LPS but increased its protein expression levels. Moreover, we found that the transcriptional signature induced by LPS was not altered between WT and mNLS macrophages. Release of IL-1 in response to different stimuli such as ionomycin was not negatively impacted by disrupted nuclear localisation, although higher levels of IL-1 release were detected, potentially due to increased levels of pro-IL-1. Inflammatory responses in an in vivo model of peritonitis and an influenza infection model were comparable between WT and mNLS mice. Thus, we have established a mouse model in which pro-IL-1 nuclear localisation is disrupted, although future research is required to reveal the importance of this nuclear localisation for IL-1 function.

immunology↗

bioRxiv2024

CCR2-driven monocyte recruitment is protective against radiotherapy-induced intestinal toxicity

Radiotherapy (RT) is essential in treating abdominal and pelvic cancers but often damages the healthy tissues, particularly the intestines, leading to radiation-induced toxicities with limited treatment options. While the immune system is known to help regulate tissue damage, immune mechanisms involved in RT-induced intestinal toxicity are not fully understood. Following CT-guided localised intestinal irradiation, single-cell RNA sequencing (scRNA-seq) and flow cytometry revealed RT-induced chemokine-dependent recruitment of innate immune cells. Deletion of C-C chemokine receptor (Ccr)1, Ccr2, Ccr3 and Ccr5, blocked recruitment and worsened radiation induced toxicities, suggesting an important role for an innate immune cell population in limiting RT-mediated bowel damage. Furthermore, CCR2-deficient mice showed exacerbated weight loss and intestinal permeability, while the transfer of Ly6C+ monocytes alleviated symptoms. Mechanistically, IL-17 cytokine production by group 3 innate lymphoid cells (ILC3s), a critical factor in maintaining intestinal barrier integrity, was found to be reduced in irradiated CCR2-/-, however the transfer of Ly6C+ monocytes resulted in increased IL-17 levels. These findings demonstrate the critical importance of CCR2-mediated monocyte recruitment in mitigating RT-induced toxicities. One Sentence SummaryCCR2-mediated monocyte recruitment protects against RT-induced intestinal toxicity via IL-17, highlighting a therapeutic target.

immunology↗

bioRxiv2023

A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross-reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+ effector memory T (TEM) cells activate the important immunoregulatory cytokine TGF{beta}, via expression of an integrin, v{beta}8. Integrin v{beta}8 expression marks a transcriptionally distinct sub-population of CD4+ TEM, enriched for anti-inflammatory pathways. Loss of integrin v{beta}8 on murine CD4+ TEM, but not Foxp3+ regulatory T cells (TREG), led to exacerbated virus-specific CD8+ T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin v{beta}8 expression on CD4+ TEM resulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of v{beta}8+ CD4+ TEM cells. These data highlight a new pathway by which a distinct CD4+ memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.

immunology↗