Biology subjects

Gonzalez-Avalos, E.

Publications and source records attributed to Gonzalez-Avalos, E..

4 recordsLinked to original sources

bioRxiv2026

The atypical IκB factor IκBδ enhances CD8 T cell accumulation and effector functions in solid tumors

Two prominent mechanisms by which tumors fend off immune control are by constraining the ability of T cells and CAR T cells to survive and expand in the tumor, and by restraining their ability to sustain full cytotoxic capacity. We identified I{kappa}B{delta}, encoded by Nfkbid, a poorly characterized I{kappa}B family member, as a molecular lever that overcomes both of these constraints on anti-tumor CD8+ tumor-infiltrating lymphocytes (TILs). Nfkbid is an NFAT target gene that is expressed in CD8+ effector T cells and, at modest levels, in CD8+ TILs. We found that Nfkbid depletion impaired TIL accumulation, exacerbating the growth of solid tumors. On the other hand, ectopic I{kappa}B{delta} overexpression enhanced TIL expansion, reduced the expression of exhaustion-associated transcription factors and inhibitory receptors, and elevated cytotoxic molecule production, leading to enhanced tumor control. I{kappa}B{delta} has a shorter protein isoform that is identical in a core region spanning the ankyrin-repeat domain known to interact with NF{kappa}B proteins, but that lacks the [~]150-residue N-terminal region. We showed that the shared core region is sufficient to drive T cell accumulation, whereas the N-terminal peptide region is required for robust effector function and to counter exhaustion, underscoring that tumor-infiltrating CD8+ T cell accumulation and effector differentiation are separable programs. Our current study provides evidence that I{kappa}B{delta}, an atypical member of the NF{kappa}B family, is a lever to overcome two cardinal deficits that limit CD8+ TIL anti-tumor efficacy: impaired accumulation in the tumor and diminished effector function.

immunology↗

bioRxiv2021

Epigenetic Remodeling by Vitamin C Potentiates the Differentiation of Mouse and Human Plasma Cells

Ascorbate (vitamin C) is an essential micronutrient in humans. The chronic severe deficiency of ascorbate, termed scurvy, has long been associated with increased susceptibility to infections. How ascorbate affects the immune system at the cellular and molecular levels remained unclear. Here, from a micronutrient screen, we identified ascorbate as a potent enhancer for antibody response by facilitating the IL-21/STAT3-dependent plasma cell differentiation in mouse and human B cells. The effect of ascorbate is unique, as other antioxidants failed to promote plasma cell differentiation. Ascorbate is critical during early B cell activation by poising the cells to plasma cell lineage without affecting the proximal IL-21/STAT3 signaling and the overall transcriptome. Consistent with its role as a cofactor for epigenetic enzymes, ascorbate potentiates plasma cell differentiation by remodeling the epigenome via TET (Ten Eleven Translocation), the enzymes responsible for DNA demethylation by oxidizing 5-methylcytosines into 5-hydroxymethylcytosine (5hmC). Genome-wide 5hmC profiling identified ascorbate responsive elements (EAR) at the Prdm1 locus, including a distal element with a STAT3 motif overlapped with a CpG that was methylated and modified by TET in the presence of ascorbate. The results suggest that an adequate level of VC is required for antibody response and highlight how micronutrients regulate the activity of epigenetic enzymes to regulate gene expression. Our findings imply that epigenetic enzymes can function as sensors to gauge the availability of metabolites and influence cell fate decisions.

immunology↗

bioRxiv2021

The transcriptional cofactor IRF2BP2 plays a key role in T cell homeostasis and Treg cell expansion

The levels of the co-transcriptional regulator IRF2BP2 (Interferon Regulatory Factor-2 Binding Protein-2) decrease with T cell activation and, when ectopically expressed, it reduces T cell proliferation. To further characterize the function of IRF2BP2 in T cell responses in vivo, we generated a conditional transgenic knock-in mouse that overexpresses IRF2BP2 in T lymphocytes. Overexpression of IRF2BP2 leads to a reduction in the T cell compartment of naive animals, upregulation of Foxp3 and Ifng; an increase in the frequency of regulatory T cells (Tregs), a preferential Th1 differentiation with increase of IFN-{gamma} production and a reduction of T cell proliferation, suggesting a disruption in T cell homeostasis. Interestingly, knock-in mice displayed reduced clinical and inflammatory signs of Experimental Autoimmune Encephalomyelitis (EAE) when compared to the control mice, with an augmented frequency of Treg cells. Altogether, our findings indicate that IRF2BP2 might help to control exacerbated T cell responses and point to a role for IRF2BP2 in preventing T cell autoimmunity.

immunology↗

bioRxiv2018

TET enzymes augment AID expression via 5hmC modifications at the Aicda superenhancer

TET enzymes are dioxygenases that promote DNA demethylation by oxidizing the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Here we report a close correspondence between 5hmC-marked regions, chromatin accessibility and enhancer activity in B cells, and a strong enrichment for consensus binding motifs for basic region-leucine zipper (bZIP) transcription factors at TET-responsive genomic regions. Functionally, Tet2 and Tet3 regulate class switch recombination (CSR) in murine B cells by enhancing expression of Aicda, encoding the cytidine deaminase AID essential for CSR. TET enzymes deposit 5hmC, demethylate and maintain chromatin accessibility at two TET-responsive elements, TetE1 and TetE2, located within a superenhancer in the Aicda locus. Transcriptional profiling identified BATF as the bZIP transcription factor involved in TET-dependent Aicda expression. 5hmC is not deposited at TetE1 in activated Batf-deficient B cells, indicating that BATF recruits TET proteins to the Aicda enhancer. Our data emphasize the importance of TET enzymes for bolstering AID expression, and highlight 5hmC as an epigenetic mark that captures enhancer dynamics during cell activation.

immunology↗