Biology subjects

Akbar, I.

Publications and source records attributed to Akbar, I..

4 recordsLinked to original sources

bioRxiv2025

Myelin antigen-specific effector CD8+ T cells induce chronic CNS autoimmunity in a CD4+ T cell-dependent manner.

Both CD4+ and CD8+ T cells play critical roles in the immunopathogenesis of multiple sclerosis (MS). 1C6 T cell receptor transgenic (TcR-Tg) mice on the nonobese diabetic (NOD) background have a MOG[35-55]-specific, MHC class II-restricted, TcR that selects for both CD4+ and CD8+ T cells. Adoptive transfer of 1C6 CD4+ T helper 17 (Th17) cells can induce experimental autoimmune encephalomyelitis (EAE) with a progressive disease course. In the current study, we assessed the function and pathogenicity of 1C6 CD8+ T cells. We found that they proliferated and produced inflammatory cytokines in response to MOG[35-55] peptide under both T cytotoxic 1 (Tc1) and Tc17 differentiation conditions, albeit with reduced expansion relative to their Th1 or Th17 counterparts. Both 1C6 Tc1 and Tc17 cells were able to induce EAE upon adoptive transfer to NOD.Scid mice. Intriguingly, we noted in vivo expansion of CD4+ T cells in the spleen and CNS of NOD.Scid recipients as well as in lymphocyte-sufficient animals, despite 1C6 Tc cells being purified on CD8 expression prior to transfer. Furthermore, 1C6 Tc17 cells expressed ThPOK, a master differentiation factor for CD4+ T cells. Finally, anti-CD4+ T cell blockade abrogated CD8+ T cell infiltration of the CNS and disease induction in Tc17 recipient mice. Our data provide insight into the interplay of CD4+ and CD8+ T cells in CNS autoimmunity.

immunology↗

bioRxiv2023

Serpine1 negatively regulates Th1 cell responses in experimental autoimmune encephalomyelitis.

Th1 cells are critical in experimental autoimmune encephalomyelitis (EAE). Serpine1 has been posited as an inhibitor of IFN{gamma} from T cells though its role in autoimmunity remains unclear. Here, we show that Serpine1 knockout (KO) mice develop EAE of enhanced severity relative to wild-type (WT) controls. Serpine1 overexpression represses Th1 cell cytokine production and pathogenicity, while Serpine1-KO:2D2 Th1 cells transfer EAE of increased severity in comparison to WT 2D2 Th1 cells. Notably, polarized Serpine1-KO Th1 cells display delayed expression of the Th1-specific inhibitory receptor, Tim-3. Serpine1-KO:Tim-3-Tg Th1 cells, which transgenically over-express Tim-3, showed increased expression of IFN{gamma} and reduced expression of the checkpoint molecules Lag-3 and PD-1 relative to WT Tim-3-Tg counterparts. Further, Serpine1 deficiency restored the EAE phenotype of Tim-3-Tg mice that normally develop mild disease. Together, we identify Serpine1 as a negative regulator of Th1 cells. Key pointsO_LISerpine1 inhibits EAE in a T cell-dependent manner. C_LIO_LISerpine1 is upregulated in Th1 cells and inhibits their pathogenicity. C_LIO_LISerpine1 promotes expression and function of Th1-specific inhibitory receptor Tim-3. C_LI

immunology↗

bioRxiv2019

Identification and classification of hubs in miRNA target gene networks in human neural stem/progenitor cells following Japanese encephalitis virus infection

Micro RNA dysregulation is observed in many viral diseases. RNA viruses modulate host miRNA machinery for their own benefit. JEV, a neurotropic RNA virus has been reported to manipulate several miRNAs in neuron or microglia. However, no report indicates a complete sketch of the miRNA profile of NSPCs contributing to viral persistence; hence being focused in our current study. We performed a miRNA array of 84 miRNAs in human neuronal progenitor cell line and primary neural precursor cells isolated from aborted foetus. Several fold down-regulation of hsa-miR-9-5p, hsa-miR-22-3p, hsa-miR-124-3p and hsa-miR-132-3p were found in both of the cells. Subsequently, we screened for the target genes of these miRNAs and looked for the important biological pathways the genes significantly regulate. Then we sorted out the target genes which are involved in two or more than two pathways. We constructed a protein-protein interaction (PPI) network of the miRNA target genes based on their interaction patterns. A binary adjacency matrix for each gene network was prepared. Different modules or communities were identified in those networks using community detection algorithms. Mathematically, we identified the hub genes by analyzing their degree centrality and participation co-efficient in the network. The hub genes were classified either as provincial (P<0.4) or connector hubs (P>0.4). We validated the expression of hub genes in both cell line and primary cells through qRT-PCR post JEV infection and respective miR-mimic transfection. Taken together, our findings highlight the importance of specific target gene networks of miRNAs affected by JEV infection in NSPCs.\n\nImportanceJEV damages the neural stem/progenitor cell population of mammalian brain. However, JEV induced alteration in miRNA expression pattern of the cell population remains an open question, hence warrants our present study. In this study, we specifically address the down-regulation of four miRNAs and we prepared a protein-protein interaction network of miRNA target genes. We identified two types of hub genes in the PPI network namely connector hubs and provincial hubs. These two types of miRNA target hub genes critically influence the participation strength in the networks and thereby significantly influence up and down regulation in several key biological pathways. Computational analysis of the PPI networks identifies key protein interactions and hubs in those modules which opens up the possibility of precise identification and classification of host factors for viral infection in NSPCs and how RNA viruses modulate host miRNA machinery for their own benefit post JEV infection to the cells.

microbiology↗

bioRxiv2018

Japanese Encephalitis Virus Infected Microglial Cells Secrete Exosomes Containing let-7a/b that Facilitate Neuronal Damage via Caspase Activation

Extracellular microRNAs (miRNAs) are essential for the cell to cell communication in the healthy and diseased brain. MicroRNAs released from the activated microglia upon neurotropic virus infection may exacerbate CNS damage. Here, we identified let-7a and let-7b (let-7a/b) as the overexpressed miRNAs in Japanese Encephalitis virus (JEV) infected microglia and assessed their role in JEV pathogenesis. We measured the let-7a/b expressions in JEV infected post-mortem human brains, mice brains and in mouse microglial N9 cells by the qRT-PCR and in situ hybridization assay. The interaction between let-7a/b and NOTCH signaling pathway further examined in Toll-like receptor 7 knockdown (TLR7 KD) mice to assess the functions. Exosomes released from JEV infected or let-7a/b mimic transfected N9, and HEK-293 cells were isolated and evaluated their function. We observed an upregulation of let-7a/b in the infected brains as well as in microglia. Knockdown of TLR7 or Inhibition of let-7a/b suppressed the JEV induced NOTCH activation possibly via NF-{kappa}B dependent manner and subsequently, attenuated JEV induced TNF production in microglial cells. Further, exosomes secreted from JEV-infected microglial cells specifically contained let-7a/b. Exosomes overexpressed with let-7a/b were injected into BALB/c mice as well as co-incubated with mouse neuronal (Neuro2a) cells, or primary cortical neuron resulted in caspase activation leading to neuronal damage in the brain. Thus, our results provide evidence for the multifaceted role of let-7a/b miRNAs and unravel the exosomes mediated mechanism for JEV induced pathogenesis.

neuroscience↗