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Rudd, B.

Publications and source records attributed to Rudd, B..

2 recordsLinked to original sources
bioRxiv2025

Humanizing a CD28 signaling domain affects CD8 activation, exhaustion and stem-like precursors

CD28 ligation provides critical signals that modulate activated T cell fate. In a human to mouse reverse-engineering approach, a single amino acid substitution adjacent to the C-terminal proline-rich domain created CD28A210P mice with enhanced signaling. CD28A210P mice experienced pro-inflammatory responses to CD28 superagonist antibody, analogous to severe cytokine storm induced in a human clinical trial, with a striking increase of activated CD8 T cells. In acute and chronic viral infections, early activation and expansion of CD28A210P CD8 effector T cells increased, with accelerated exhaustion in chronic infection. Mechanistically, CD28A210P enhanced JunB, IL-2, and inhibitory receptors driven by MEK1/2. Generation of CD28A210P stem-like progenitor (Tpex) cells was enhanced in acute and chronic infections, and further expanded by PD-L1 blockade in chronically-infected mice. Thus, humanized PYAP mice reveal key roles for CD28 signaling strength in CD8 activation, accelerating exhaustion during antigen persistence, while promoting and sustaining Tpex during acute and chronic viral infection. One sentence SummaryA single amino acid substitution adjacent to PYAP to humanize CD28 signaling enhances superagonist response, early CD8 activation and Tpex generation during viral infection while accelerating exhaustion and sustaining Tpex during chronic infection. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/642460v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@13fc9f9org.highwire.dtl.DTLVardef@e50762org.highwire.dtl.DTLVardef@47c8eeorg.highwire.dtl.DTLVardef@d892d7_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Humanized CD28 PYAPP enhances numbers of CD8 T cell effectors and stem-like precursors during acute viral infection, and accelerates exhaustion while sustaining increased self-renewing Tpex cells that are favored during PD-L1 blockade. C_FIG

immunology↗
bioRxiv2022

Lin28b specifies an innate-like lineage of CD8+ T cells in early life

The immune system is stratified into layers of specialized cells with distinct functions. Recently, Lin28b was shown to serve as a master regulator of fetal lymphopoiesis, programming the development of more innate-like lymphocytes in early life. However, it remains unclear whether Lin28b specifies innate functions in more conventional adaptive lymphocytes. In this report, we discovered that Lin28b promotes the development of a more innate-like lineage of CD8+ T cells that is capable of protecting the host against a wide variety of pathogens in the absence of TCR stimulation. Using RNA-seq and ATAC-seq, we found that Lin28b transcriptionally and epigenetically programs CD8+ T cells to be highly responsive to innate cytokines. We also performed scRNAseq and found that the shift from innate-like CD8+ T cells in early life to adaptive CD8+ T cells in adulthood is mediated by changes in the abundance of distinct subsets of cells. Remarkably, the innate CD8+ T cell subset predominates in early life but is also present in adult mice and humans. Collectively, our findings demonstrate that neonatal CD8+ T cells are a distinct lineage of lymphocytes that provide the host with innate defense in early life. One sentence SummaryHigh-dimensional analysis reveals how Lin28b programs neonatal CD8+ T cells for innate defense.

immunology↗