Biology subjects

Pobezinsky, L. A.

Publications and source records attributed to Pobezinsky, L. A..

2 recordsLinked to original sources

bioRxiv2025

Heterogeneity of CD8αα intraepithelial lymphocytes is transcriptionally conserved between TCRαβ and TCRγδ cell lineages.

Intestinal intraepithelial lymphocytes (IELs) are a versatile population of immune cells with both effector and regulatory roles in gut immunity. Although this functional diversity is thought to arise from distinct IEL subpopulations, the heterogeneity of TCR{beta}+ and TCR{gamma}{delta}+ IELs have not been well-characterized. Using scRNAseq, we identified CD8+ T cell subsets with memory-like (Tcf7) and effector-like (Prdm1) profiles in both TCR{beta}+ and TCR{gamma}{delta}+ IELs. Using CD160 and CD122 as markers of memory-like and effector-like cells, respectively, we found that while effector-like cells dominated the small intestine, memory-like IELs were more prevalent in the large intestine, suggesting a functional specialization of immune responses along the gut. Further transcriptional analysis revealed shared profiles between TCR{beta}+ and TCR{gamma}{delta}+ small intestinal IEL subsets, suggesting conserved functional roles across these populations. Finally, our analysis indicated that TCR{beta}+ memory-like IELs arise from Tcf7 double-negative (DN) precursors, and that effector-like IELs subsequently differentiate from the memory-like population. In contrast, TCR{gamma}{delta}+ IELs appear to originate from two distinct precursor populations, one expressing Tcf7 and the other Zeb2, indicating the presence of parallel developmental pathways within this lineage. Overall, our findings reveal that both TCR{beta}+ and TCR{gamma}{delta}+ cells contain memory-like and effector-like subsets, which may contribute to the functional heterogeneity of IELs.

immunology↗

bioRxiv2025

A Dapl1+ subpopulation of naive CD8 T cells contains committed precursors of memory lineage.

Memory CD8 T cells play a vital role in providing lasting immune protection, yet their origins remain incompletely understood. Contrary to classical models, emerging evidence suggests that heterogeneity within the naive T cell pool may influence fate decisions prior to antigen encounter. However, the markers of naive T cell heterogeneity have not yet been clearly defined. Here, we describe intraclonal heterogeneity within the naive T cell population marked by the protein Dapl1. Using novel monoclonal antibodies and a reporter-knockout mouse model, we found that Dapl1-positive naive CD8 T cells exhibit distinct phenotypes compared to their Dapl1-negative counterparts. Furthermore, this population includes a subset of pre-programmed precursors biased toward memory lineage fate. The differentiation of these precursors is independent of Dapl1 but relies on the transcription factor Bcl11b, resulting in the generation of Dapl1-positive central memory-like CD8 T cells in response to infection, and stem-like memory cells in response to cancer. Notably, naive Dapl1-positive T cells originate among mature thymocytes and gradually appear in the periphery within several days after birth. Our findings suggest that committed memory precursors in the Dapl1-positive population may represent an alternative pathway for memory CD8 T cell generation, offering new avenues for therapeutic application. ONE-SENTENCE SUMMARYNaive Dapl1 positive CD8 T cells include a pre-programmed subset biased toward differentiation into memory-like T cells.

immunology↗