Tchitcheck, N. | bioRxiv Science

bioRxiv2023

Interleukin-1 regulates follicular T cells during the germinal center reaction

Antibody production by plasma cells and generation of long-term memory B-cells are positively regulated by Tfh cells and negatively regulated by Tfr cells in germinal centers. However, the precise role of Tfr cells in controlling antibody production is still unclear. We have previously shown that Tfh and Tfr cells both express IL-1R1, while only Tfr cells express the IL-1R2 decoy and IL-1Ra antagonist receptors. To study the role of these receptors in the regulation of the B cell response by Tfh and/or Tfr cells, we generated mice with knockout of IL-1 receptors in Tfh and/or Tfr cells and measured antibody production and cell activation upon immunization. We showed that IL-1{beta} concentration is increased in the draining lymph node after immunization. Antigen-specific antibody levels and cell activation phenotypes indicated that IL-1{beta} can activate both Tfh and Tfr cells through IL-1R1 stimulation. Surprisingly, IL-1R2 and IL-1Ra expression on Tfr cells does not block IL-1 activation of Tfh cells, but rather prevents IL-1/IL-1R1-mediated early activation of Tfr cells. IL-1Rs similarly regulate antibody response against autoantigens and its related pathophysiology in an experimental lupus model. Altogether, these results show that IL-1R1 inhibitory receptors expressed by Tfr cells prevent their own activation and suppressive function, thus licensing IL-1-mediated activation of Tfh cells after immunization. One Sentence SummaryFunctional knockout of IL-1 agonist (R1) and antagonist (R2 and Ra) receptors reveals that IL-1-R2 and -Ra on Tfr cells prevent their own early activation to license the expansion and activation of Tfh cells after immunization.

immunology↗

bioRxiv2021

Network topology and evolution of the gene co-expression of T-cells during immuno-senescence

To better understand the potential impact of the gene expression network structure on the dynamics of immune-senescence and defects of cell functions during aging, we investigated network structures in both young and old individuals. We analyzed the gene co-expression networks (GCNs) derived from an aging signature of 130 immune-related genes obtained from CD3+ T-cell splenocytes extracted from FVB/N, C57BL/6N, and BALB/c mice at ages 2 and 22- 24 months. The network structure for the two different mouse age-groups was derived and subsequently analyzed. Analysis of network hubs using clustering coefficients, degree, betweenness, eigenvector, and closeness centralities, as well as local, indirect, and total influence measures, demonstrated changes in gene behavior and network control between the two age groups. Our quantification shows that the young, 2-month old mouse network is more organized than the 22-24-month, old mouse network, while the network structure of the older mouse GCN appears to be far more complicated but far more dispersed. Changes in network structure between the old and young mice suggest deterioration in transcription regulation with age in peripheral T- cells, particularly within the TCR signaling pathway, and potential compensatory mechanisms in older T-cells to overcome loss to regular function resulting from transcriptional irregularity. These results demonstrate the need for more research into gene co-expression in peripheral T-cells in order to better understand both network irregularities and the phenotypic dysfunction observed in older individuals. Author SummaryIn order to better understand the potential mechanisms of transcriptional irregularities in the immune system with aging, we analyzed the structure of gene co-expression networks of T-cells extracted from the spleens of 2 and 22-24-month old mice. Gene co-expression describes the correlation relationship between two expressed genes; as the expression of one gene goes up, the expression of another gene might also increase (or, conversely, decrease). Strong gene co- expression relationships can signal the existence of a number of important biological phenomena, such as two genes belonging to a transcription pathway or protein structure. Network diagrams visualizing these co-expression relationships in both younger and older mice demonstrated the existence of differences in network structure and properties that may be attributed to the aging of the immune system. Network mathematical methods were used to examine the complexity of each network. We found that the younger mouse network was more organized than the older mouse network. The older mouse group exhibited a 255% increase in co-expression relationships but a decrease of 92% of the connections from the young mouse network. This suggests the older mouse T-cells suffer dysfunction at a transcriptional level. This results in the loss of regular immune and cellular functions. These results demonstrate the importance of future research into gene co-expression to decipher senescence or diseases that perturb gene expression through time.

systems biology↗