Biology subjects

Su, L. F.

Publications and source records attributed to Su, L. F..

5 recordsLinked to original sources

bioRxiv2026

Serial vaccination expands and refines human CD4+ T cell memory

CD4+ T cells coordinate protective immunity against pathogens. However, a major unresolved question is how human CD4+ T cell memory is established and evolves following primary and repeated vaccination. Using COVID-19 mRNA vaccination as a model, we tracked 50 distinct antigen-specific populations directly ex vivo with peptide-MHC class II tetramers in eight SARS-CoV-2-naive individuals from pre-vaccine baseline through memory time points after three mRNA doses. Our findings identify the primary vaccine series as the main driver of memory pool size. It leverages pre-existing memory while preferentially recruiting high-avidity T cells, establishing an immunodominance hierarchy dominated by a small subset of precursors. Booster vaccination refines both the magnitude and quality of T cell memory. It increases select populations and enhances differentiation of subdominant CD4+ T cells. Populations that did not become more abundant after boosting retained their polyfunctional potential. Beyond establishing memory to the ancestral spike, vaccinations broadened responses by recruiting cross-reactive T cells recognizing viral variants. Collectively, these findings reveal how human CD4+ T cell memory evolves through sequential immunizations to generate a functionally diverse and broadly responsive memory repertoire against future viral challenges.

immunology↗

bioRxiv2024

Divergent effects of cytomegalovirus and rheumatoid arthritis on senescent CD4+ T cells

CD4+ T cell senescence has been linked to repeated antigen stimulation. However, how different types of chronic antigenic exposures impact T cell differentiation and function remains incompletely understood. Using rheumatoid arthritis (RA) and cytomegalovirus (CMV) as models for persistent stimulation in autoimmunity and chronic viral infection, we performed high-dimensional mass cytometry analyses to examine their effects on CD4+ T cell differentiation. We found that CMV seropositive adults have a significant population of highly differentiated CD27-CD28-CD4+ T cells that exhibited common features of senescence, including CD57 and cytotoxic granule expression. In contrast, CD27-CD28-CD4+ T cells were rare in RA patients and Epstein-Barr virus (EBV) or Herpes simplex virus (HSV) seropositive individuals. The few that were present exhibited a predominantly non-cytotoxic profile, with higher expression of TCF1, CD127, and Ki67. Among CMV seropositive individuals, RA was associated with reduced degranulation of cytotoxic granules and lower cytokine production by senescent CD4+ T cells. We did not find an association with age, sex, clinical characteristics, or medication usage by univariate linear regression analyses. However, in vitro tofacitinib treatment reduced T cell functional activity, suggesting contributions from both the disease and RA treatment. These data uncovered distinct influences from CMV and RA, and their combined impact on senescent CD4+ T cell differentiation and function.

immunology↗

bioRxiv2024

Differentiation marker-negative CD4+ T cells persist after yellow fever virus vaccination and contribute to durable memory

Factors that contribute to durable immunological memory remain incompletely understood. In our longitudinal analyses of CD4+ T cell responses to the yellow fever virus (YFV) vaccine by peptide-MHC tetramers, we unexpectedly found naive phenotype virus-specific CD4+ T cells that persisted months to years after immunization. These Marker negative T cells (TMN) lacked CD95, CXCR3, CD11a, and CD49d surface protein expression, distinguishing them from previously discovered stem-cell memory T cells. Functionally, they resembled genuine naive T cells upon in vitro stimulation. Single-cell TCR sequencing detected expanded clonotypes within the TMN subset and identified a shared repertoire with memory and effector T cells. T cells expressing TMN-associated TCRs were rare before vaccination, suggesting their expansion following vaccination. Longitudinal tracking of YFV-specific responses over the subsequent years revealed superior stability of the TMN subset and their association with the longevity of the overall population. The identification of these long-lived, antigen-experienced T cells may inform the design of durable T cell-based vaccines and engineered T cell therapies.

immunology↗

bioRxiv2020

Vaccination reshapes the virus-specific T cell repertoire in unexposed adults

How baseline T cell characteristics impact human T cell responses to novel pathogens remains unknown. Here, we address this question by studying the CD4+ T cell response in unexposed individuals to live attenuated yellow fever virus (YFV) vaccine. We quantified virus-specific population dynamics over time using class II peptide-MHC tetramers. Our data revealed that, even in the absence of known viral exposure, memory phenotype T cells were found in the majority of virus-specific precursors in healthy adults. Pre-existing memory T cells can be divided into two groups; abundant pre-vaccine populations that underwent limited overall expansion and rare cells that generated naive-like responses and preferentially contributed to the memory repertoire after vaccination. Single cell T cell receptor (TCR) sequencing was used to track the evolution of immune responses to different epitopes and showed an association between preservation of unexpanded TCRs before exposure and the robustness of post-vaccine responses. Instead of a further increase in pre-established TCR clones, vaccination boosted the representation of rare TCRs. Thus, vaccine restructures the abundance and clonal hierarchy of virus-specific T cells. Our results link T cell precursor states to post-exposure responses, identifying peripheral education of virus-specific repertoire as a key component of effective vaccination. {circ}YFV-specific precursors contain abundant memory phenotype cells in healthy adults. {circ}Precursor frequency and phenotype are linked to post-immune response. {circ}Vaccination recruits rare virus-specific populations. {circ}Vaccination overrides pre-established clonal hierarchy

immunology↗

bioRxiv2019

Mapping the lineage relationship between CXCR5+ and CXCR5- CD4+ T cells in HIV infected human lymph nodes

CXCR5 is a key surface marker expressed on follicular helper T (TFH) cells. We report here B cell help functionality in a population of CD4+ T cells isolated from primary human lymph nodes (LN) that lacked CXCR5 expression. This CXCR5- subset is distinguished from other CXCR5- CD4+ T cells by high PD-1 expression. Accumulation of CXCR5-PD-1+ T cells correlated with peripheral CD4+ T cell depletion and an increase in T-bet+ B cells in the LN, highlighting these atypical CD4+ T cells as a key component of lymphoid dysregulation during chronic HIV infection. By interrogating the phenotypic heterogeneity, functional capacity, TCR repertoire, transcriptional profile, and epigenetic state of CXCR5-PD-1+ T cells, we showed that CXCR5-PD-1+ T cells are related to CXCR5+PD-1+ T cells and provided evidence for the down regulation of CXCR5 following cell division as one mechanism for the absence of CXCR5 expression. Notably, CXCR5-PD-1+ T cells exhibited a migratory transcriptional program and contributed to circulating CXCR5-PD-1+ T cells with B cell help functionality in the peripheral blood. Thus, these data link LN pathology to circulating T cells and expand the current understanding on T cell diversity in the regulation of B cell responses during chronic inflammation. O_LIHigh dimensional profiling of activated CD4+ T cells in HIV infected lymph nodes revealed an accumulation of a CXCR5 negative subset. C_LIO_LICXCR5-PD-1+CD4+ T cells exhibited TFH-like protein expression and function. C_LIO_LICXCR5-PD-1+CD4+ T cells are related to TFH cells by clonal lineage and epigenetic similarity. C_LIO_LICXCR5-PD-1+CD4+ T cells upregulate a migratory gene program and contribute to circulating T cells with B cell help functionality C_LI

immunology↗