Diphenylcyclopropenone (DPC) is an organic chemical hapten which induces allergic contact dermatitis, and is used in treatment of warts, melanoma and alopecia areata. This therapeutic setting therefore provided an opportunity to study T cell receptor (TCR) repertoire changes in response to hapten sensitization in humans. Repeated exposure to DPC induced highly dynamic transient expansions of a polyclonal diverse T cell population. The number of TCRs expanded early after sensitization varies between individuals, and predicts the magnitude of the allergic reaction. The expanded TCRs show preferential TCR V and J gene usage, and consist of clusters of TCRs with similar sequences, two characteristic features of antigen-driven responses. The expanded TCRs share subtle sequence motifs that can be captured using a Dynamic Bayesian Network. These observations suggest the response to DPC is mediated by a polyclonal population of T cells recognizing a small number of dominant antigens.
All DNA sequences have been submitted to the Short Read Archive under identifier SUB6567504 .
- Benny Chain
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: The protocol was approved by the University College London Hospital Ethics Committee 06/Q0502/92. A total of 34 patients were recruited to this study (NRES Ethics Committee East of England - Cambridgeshire and Hertfordshire [14/EE/1067]). Participants were recruited from patients who had been diagnosed with alopecia, were aged between 18 and 70, identified as suitable for DPC treatment by a consultant dermatologist, and were now attending their first visit to the Alopecia Clinic at Salford Royal Hospital for DPC therapy. This study ran alongside patients' prescribed DPC treatment (weekly doses of DPC to the scalp to induce inflammation and hair regrowth). All participants gave their informed consent to participate, and were free to withdraw from the study at any time and for any reason without affecting their treatment. Patients were excluded from the study if they were pregnant.
- Armita Nourmohammad, University of Washington, United States
© 2021, Ronel et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology, however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.
T cells are required to clear infection, and T cell motion plays a role in how quickly a T cell finds its target, from initial naive T cell activation by a dendritic cell to interaction with target cells in infected tissue. To better understand how different tissue environments affect T cell motility, we compared multiple features of T cell motion including speed, persistence, turning angle, directionality, and confinement of T cells moving in multiple murine tissues using microscopy. We quantitatively analyzed naive T cell motility within the lymph node and compared motility parameters with activated CD8 T cells moving within the villi of small intestine and lung under different activation conditions. Our motility analysis found that while the speeds and the overall displacement of T cells vary within all tissues analyzed, T cells in all tissues tended to persist at the same speed. Interestingly, we found that T cells in the lung show a marked population of T cells turning at close to 180o, while T cells in lymph nodes and villi do not exhibit this “reversing” movement. T cells in the lung also showed significantly decreased meandering ratios and increased confinement compared to T cells in lymph nodes and villi. These differences in motility patterns led to a decrease in the total volume scanned by T cells in lung compared to T cells in lymph node and villi. These results suggest that the tissue environment in which T cells move can impact the type of motility and ultimately, the efficiency of T cell search for target cells within specialized tissues such as the lung.