About

Leonid A. Pobezinsky, PhD, is an Associate Professor leading the Pobezinsky Lab at UMASS Amherst. His research focuses on the regulation of the immune response, with the primary goal of uncovering the molecular mechanisms that control productive versus non-productive immune responses against cancer and infection. Specifically, his lab investigates the role of regulatory non-coding RNAs in the maintenance and differentiation of T cells. This work aims to deepen the understanding of immune system regulation at the molecular level, which has important implications for immunology and therapeutic development.

Research topics

• Immunology
• Biology
• Cell biology
• Cancer research
• Genetics
• Computational biology
• Biochemistry
• Medicine

Selected publications

• Antagonistic Pleiotropy Framework for the Discovery of Molecular Mechanisms of Aging

  Preprints.org · 2026-04-06

  preprintOpen access

  The antagonistic pleiotropy (AP) mechanism of aging was first proposed by G.C. Williams in 1957. However, practical application of this theory for the targeted search of longevity interventions has lagged, owing to a lack of clear understanding of the conditions under which the same gene or trait may have opposite effects on fitness in young versus old organisms. We propose that changes in the somatic environment may result from allometric growth, physiological differences between adult and juvenile life stages beyond those caused by aging, and ontogenetic niche shifts, and we provide well-documented examples of AP mechanisms corresponding to these conditions. We then test this understanding through testable predictions. Specifically, we demonstrate that (1) traits that have diverged the most between developmental stages contribute the most to aging; (2) organisms with negligible senescence exhibit minimal differences between adult and juvenile life stages; and (3) among taxonomically close organisms, stronger differences between adult and juvenile stages are associated with higher aging rates, while greater similarity is associated with lower aging rates. This understanding opens opportunities for the targeted identification of AP mechanisms based on the analysis of organisms' developmental trajectories. Additionally, it suggests two potential approaches for mitigating AP: suppression of adverse genes or traits in late life, or prevention or reversal of alterations in the somatic environment that convert previously beneficial traits into detrimental ones.

  PublisherDOI

• A Dapl1 ⁺ subpopulation of naïve CD8 T cells is enriched for memory-lineage precursors

  Science Advances · 2025-08-22 · 1 citations

  articleOpen accessSenior authorCorresponding

  Memory CD8 T cells provide long-lasting immunity, but their developmental origins remain incompletely defined. Growing evidence suggests that functional heterogeneity exists within the naïve T cell pool, shaping lineage potential before antigen stimulation. Here, we identify a subpopulation of naïve CD8 T cells expressing death-associated protein-like 1 (Dapl1) that contains preprogrammed precursors biased toward memory differentiation. The differentiation of these precursors is independent of Dapl1 but relies on the transcription factor B-cell lymphoma/leukaemia 11b (Bcl11b), resulting in the generation of Dapl1 + central memory–like CD8 T cells after infection and stem-like memory cells in cancer. Dapl1 + naïve T cells originate among mature thymocytes and gradually appear in the periphery postnatally. Peripheral Dapl1 + and Dapl1 − populations show limited plasticity, supporting a thymic-imprinting model. These findings reveal a developmentally imprinted subset of naïve CD8 T cells committed to memory fate, uncovering an alternative pathway for memory T cell generation offering new avenues for therapeutic application.

  PublisherDOI

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

  Frontiers in Immunology · 2025-08-05 · 3 citations

  articleOpen accessSenior authorCorresponding

  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 TCRαβ + and TCRγδ + IELs have not been well characterized. Using scRNAseq, we identified CD8αα + T cell subsets with memory-like ( Tcf7 + ) and effector-like ( Prdm1 + ) profiles in both TCRαβ + and TCRγδ + 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 TCRαβ + and TCRγδ + small intestinal IEL subsets, suggesting conserved functional roles across these populations. Finally, our analysis indicated that TCRαβ + memory-like IELs arise from Tcf7 + double-negative (DN) precursors, and that effector-like IELs subsequently differentiate from the memory-like population. In contrast, TCRγδ + 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 TCRαβ + and TCRγδ + cells contain memory-like and effector-like subsets, which may contribute to the functional heterogeneity of IELs.

  PublisherOA PDFDOI

• Heterogeneity of CD8αα intraepithelial lymphocytes is transcriptionally conserved between TCRαβ and TCRγδ cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-25

  preprintOpen accessSenior authorCorresponding

  Abstract 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 TCRαβ + and TCRγδ + IELs have not been well-characterized. Using scRNAseq, we identified CD8αα + T cell subsets with memory-like ( Tcf7 ⁺) and effector-like ( Prdm1 ⁺) profiles in both TCRαβ + and TCRγδ + 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 TCRαβ + and TCRγδ + small intestinal IEL subsets, suggesting conserved functional roles across these populations. Finally, our analysis indicated that TCRαβ + memory-like IELs arise from Tcf7⁺ double-negative (DN) precursors, and that effector-like IELs subsequently differentiate from the memory-like population. In contrast, TCRγδ + 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 TCRαβ + and TCRγδ + cells contain memory-like and effector-like subsets, which may contribute to the functional heterogeneity of IELs.

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-08 · 2 citations

  preprintSenior authorCorresponding

  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 in the thymus 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.

  PublisherDOI

• Angiogenic CD8 T cells from PWH induce Granzymes-dependent PAR1 activation promoting endothelial inflammation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-08

  preprintOpen access

  Abstract In people with HIV (PWH), T cell immune activation and endothelial inflammation are contributors of the increased cardiovascular risk, however the mechanisms remain poorly understood. PAR1 connects the coagulation cascade, endothelial cells and CD8 T cells at the site of endothelial inflammation and we hypothesized that HIV driven CD8 T cell immune activation alters endothelial repair mechanisms. Endothelial repair is partially mediated by angiogenic T (T ang ) cells that facilitate proliferation of endothelial cells, and differentiation of endothelial progenitor cells at site of vascular injury. During LCMV infection, we identified a subset of CD31 high CD8 T cells that exhibited a long-lived memory precursor phenotype (CD127 + KLRG1 - ) and secreted the proangiogenic cytokine vascular endothelial growth factor (VEGF) after viral control. Furthermore, in PWH, the frequencies of CD8 T ang cells were reduced and showed an activated phenotype and expression of granzymes. GZMA + GZMB + CD8 T ang cells correlated with atherosclerotic cardiovascular disease (ASCVD) risk. In vitro , granzyme dependent PAR1 activation led to calcium mobilization and secretion of proinflammatory cytokines IL-6, IL-8 and angiopoietin-2 by primary human endothelial cells. Altogether, these findings suggest that CD8 T cells are involved in immunity against viruses and endothelial homeostasis and HIV driven immune activation alters these functions.

  PublisherOA PDFDOI

• TATA-binding associated factors have distinct roles during early mammalian development

  Developmental Biology · 2024-04-07 · 8 citations

  articleOpen access
  PublisherOA PDFDOI

• Tata-Binding Associated Factors are Essential for Distinct Roles During Early Mammalian Development

  SSRN Electronic Journal · 2024-01-01

  preprintOpen access
  PublisherDOI

• The mosquito effect: regulatory and effector T cells acquire cytoplasmic material from tumor cells through intercellular transfer

  Frontiers in Immunology · 2023-12-20 · 2 citations

  articleOpen accessCorresponding

  The phenomenon of intercellular transfer of cellular material, including membranes, cytoplasm, and even organelles, has been observed for decades. The functional impact and molecular mechanisms of such transfer in the immune system remain largely elusive due to the absence of a robust in vivo model. Here, we introduce a new tumor mouse model, where tumor cells express the soluble ultra-bright fluorescent protein ZsGreen, which allows detection and measurement of intercellular transfer of cytoplasm from tumor cells to infiltrating immune cells. We found that in addition to various types of myeloid lineage cells, a large fraction of T regulatory cells and effector CD8 T cells acquire tumor material. Based on the distribution of tumor-derived ZsGreen, the majority of T cells integrate captured cytoplasm into their own, while most myeloid cells store tumor material in granules. Furthermore, scRNA-seq analysis revealed significant alterations in transcriptomes of T cells that acquired tumor cell cytoplasm, suggesting potential impact on T cell function. We identified that the participation of T cells in intercellular transfer requires cell-cell contact and is strictly dependent on the activation status of T lymphocytes. Finally, we propose to name the described phenomenon of intercellular transfer for tumor infiltrating T cells the “mosquito effect”.

  PublisherOA PDFDOI

• LKB1 isoform expression modulates T cell plasticity downstream of PKCθ and IL-6

  Molecular Immunology · 2023-04-03 · 4 citations

  articleOpen access

  Following activation, CD4 T cells undergo metabolic and transcriptional changes as they respond to external cues and differentiate into T helper (Th) cells. T cells exhibit plasticity between Th phenotypes in highly inflammatory environments, such as colitis, in which high levels of IL-6 promote plasticity between regulatory T (Treg) cells and Th17 cells. Protein Kinase C theta (PKCθ) is a T cell-specific serine/threonine kinase that promotes Th17 differentiation while negatively regulating Treg differentiation. Liver kinase B1 (LKB1), also a serine/threonine kinase and encoded by Stk11, is necessary for Treg survival and function. Stk11 can be alternatively spliced to produce a short variant (Stk11S) by transcribing a cryptic exon. However, the contribution of Stk11 splice variants to Th cell differentiation has not been previously explored. Here we show that in Th17 cells, the heterogeneous ribonucleoprotein, hnRNPLL, mediates Stk11 splicing into its short splice variant, and that Stk11S expression is diminished when Hnrnpll is depleted using siRNA knock-down approaches. We further show that PKCθ regulates hnRNPLL and, thus, Stk11S expression in Th17 cells. We provide additional evidence that exposing induced (i)Tregs to IL-6 culminates in Stk11 splicing downstream of PKCθAltogether our data reveal a yet undescribed outside-in signaling pathway initiated by IL-6, that acts through PKCθ and hnRNPLL to regulate Stk11 splice variants and facilitate Th17 cell differentiation. Furthermore, we show for the first time, that this pathway can also be initiated in developing iTregs exposed to IL-6, providing mechanistic insight into iTreg phenotypic stability and iTreg to Th17 cell plasticity.

  PublisherDOI

Frequent coauthors

• Alfred Singer

  National Institutes of Health

  30 shared

• François Van Laethem

  Centre Hospitalier Universitaire de Montpellier

  21 shared

• Terry I. Guinter

  National Institutes of Health

  18 shared

• Susanna Jeurling

  Johns Hopkins University

  16 shared

• Xuguang Tai

  Hulunbuir University

  14 shared

• Jung‐Hyun Park

  Chungnam National University

  13 shared

• Susan O. Sharrow

  National Cancer Institute

  13 shared

• Motoko Y. Kimura

  Chiba University

  12 shared

Labs

• Pobezinsky LabPI