Biology subjects

Erickson, J. R.

Publications and source records attributed to Erickson, J. R..

3 recordsLinked to original sources

bioRxiv2024

Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface

Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-{beta}1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.

immunology↗

bioRxiv2021

Convergent clonal selection of donor- and recipient-derived CMV-specific T cells in hematopoietic stem cell transplant patients

Competition between antigen-specific T cells for peptide:MHC (p:MHC) complexes shapes the ensuing T cell response. Mouse model studies provided compelling evidence that competition is a highly effective mechanism controlling the activation of naive T cells. However, assessing the effect of T cell competition in the context of a human infection requires defined pathogen kinetics and trackable naive and memory T cell populations of defined specificity. A unique cohort of non-myeloablative hematopoietic stem cell transplant (nmHSCT) patients allowed us to assess T cell competition in response to CMV reactivation, which was documented with detailed virology data. In our cohort, HSCT donors and recipients were CMV-seronegative and -positive, respectively, thus providing genetically distinct memory and naive T cell populations. We used single-cell transcriptomics to track donor versus recipient-derived T cell clones over the course of 90 days. We found that donor-derived T cell clones proliferated and expanded substantially following CMV-reactivation. However, for immunodominant CMV epitopes, recipient-derived memory T cells remained the overall dominant population. This dominance was maintained despite more robust clonal expansion of donor-derived T cells in response to CMV reactivation. Interestingly, the donor-derived T cells that were recruited into these immunodominant memory populations shared strikingly similar TCR properties with the recipient-derived memory T cells. This selective recruitment of identical and nearly identical clones from the naive into the immunodominant memory T cell pool suggests that competition does not interfere with rejuvenating a memory T cell population, but results in selection of convergent clones to the memory T cell pool. SignificanceAn existing memory T cell population specific for a single epitope is sufficient to effectively curtail responses to any new antigens if the original epitope is present in a vaccination regimen or heterologous infections. We asked if T cell competition precludes recruitment of any new, naive T cells to an existing memory T cell pool in context of CMV-specific T cell responses in a cohort of transplant patients. Our data indicate that competition does not prevent recruitment of naive T cells into the memory T cell pool, but selects for T cells with nearly or fully congruent T cell receptor specificities. We discuss the implications of rejuvenating a memory T cell pool while preserving the T cell receptor repertoire.

immunology↗

bioRxiv2019

A targeted multi-omic analysis approach measures protein expression and low abundance transcripts on the single cell level

High throughput single-cell RNA sequencing (sc-RNAseq) has become a frequently used tool to assess immune cell function and heterogeneity. Recently, the combined measurement of RNA and protein expression by sequencing was developed, which is commonly known as CITE-Seq. Acquisition of protein expression data along with transcriptome data resolves some of the limitations inherent to only assessing transcript, but also nearly doubles the sequencing read depth required per single cell. Furthermore, there is still a paucity of analysis tools to visualize combined transcript-protein datasets.\n\nHere, we describe a novel targeted transcriptomics approach that combines analysis of over 400 genes with simultaneous measurement of over 40 proteins on more than 25,000 cells. This targeted approach requires only about 1/10 of the read depth compared to a whole transcriptome approach while retaining high sensitivity for low abundance transcripts. To analyze these multi-omic transcript-protein datasets, we adapted One-SENSE for intuitive visualization of the relationship of proteins and transcripts on a single-cell level.

immunology↗