Long coronavirus disease (COVID) is a heterogeneous clinical condition of uncertain etiology triggered by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we used ultrasensitive approaches to profile the immune system and the plasma proteome in healthy convalescent individuals and individuals with long COVID, spanning geographically independent cohorts from Sweden and the United Kingdom. Symptomatic disease was not consistently associated with quantitative differences in immune cell lineage composition or antiviral T cell immunity. Healthy convalescent individuals nonetheless exhibited higher titers of neutralizing antibodies against SARS-CoV-2 than individuals with long COVID, and extensive phenotypic analyses revealed a subtle increase in the expression of some co-inhibitory receptors, most notably PD-1 and TIM-3, among SARS-CoV-2 nonspike-specific CD8+ T cells in individuals with long COVID. We further identified a shared plasma biomarker signature of disease linking breathlessness with apoptotic inflammatory networks centered on various proteins, including CCL3, CD40, IKBKG, IL-18 and IRAK1, and dysregulated pathways associated with cell cycle progression, lung injury and platelet activation, which could potentially inform the diagnosis and treatment of long COVID.
© 2025. The Author(s).

There is great need for vaccines against tuberculosis (TB) more efficacious than the licensed BCG. Our goal was to identify new vaccine benchmarks by identifying immune responses that distinguish individuals able to eradicate the infection (TB-resisters) from individuals with latent infection (LTBI-participants). TB-resisters had higher frequencies of circulating CD8+ glucose monomycolate (GMM)+ Granzyme-B+ T cells than LTBI-participants and higher proportions of polyfunctional conventional and nonconventional T cells expressing Granzyme-B and/or PD-1 after ex vivo M. tuberculosis stimulation of blood mononuclear cells. LTBI-participants had higher expression of activation markers and cytokines, including IL10, and IFNγ. An exploratory analysis of BCG-recipients with minimal exposure to TB showed absence of CD8+GMM+Granzyme-B+ T cells, lower or equal proportions of Granzyme-B+PD-1+ polyfunctional T cells than TB-resisters and higher or equal than LTBI-participants. In conclusion, high Granzyme-B+PD-1+ T cell responses to M. tuberculosis and, possibly, of CD8+GMM+Granzyme-B+ T cells may be desirable for new TB vaccines.
© 2023 The Authors.

Germinal centers (GC) are critically important for maturation of the antibody response and generation of memory B cells, processes that form the basis for long-term protection from pathogens. GCs only occur in lymphoid tissue, such as lymph nodes, and are not present in blood. Therefore, GC B cells and GC T follicular helper (TFH) cells are not well-studied in humans under normal healthy conditions, due to the limited availability of healthy lymph node samples. We used a minimally invasive, routine clinical procedure, lymph node fine needle aspirations (LN FNAs), to obtain LN cells from healthy human subjects. This study of 73 LNs demonstrates that human LN FNAs are a safe and feasible technique for immunological research, and suggests benchmarks for human GC biology under noninflammatory conditions. The findings indicate that assessment of the GC response via LN FNAs will have application to the study of human vaccination, allergy, and autoimmune disease.
Copyright © 2020 Elsevier B.V. All rights reserved.

While the human fetal immune system defaults to a program of tolerance, there is concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown.
We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with pro-inflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared to healthy term controls.
We identified a transcriptionally distinct population of CD4+ T cells characterized by expression of the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF). PLZF+ CD4+ T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced pro-inflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFNγ in a fetal-specific manner. IFNγ-producing PLZF+ CD4+ T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation.
Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies.

In a large proportion of cancer patients, CD8 T cells are excluded from the vicinity of cancer cells. The inability of CD8 T cells to reach tumor cells is considered an important mechanism of resistance to cancer immunotherapy. We show that, in human lung squamous-cell carcinomas, exclusion of CD8 T cells from tumor islets is correlated with a poor clinical outcome and with a low lymphocyte motility, as assessed by dynamic imaging on fresh tumor slices. In the tumor stroma, macrophages mediate lymphocyte trapping by forming long-lasting interactions with CD8 T cells. Using a mouse tumor model with well-defined stromal and tumor cell areas, macrophages were depleted with PLX3397, an inhibitor of colony-stimulating factor-1 receptor (CSF-1R). Our results reveal that a CSF-1R blockade enhances CD8 T cell migration and infiltration into tumor islets. Although this treatment alone has minor effects on tumor growth, its combination with anti-PD-1 therapy further increases the accumulation of CD8 T cells in close contact with malignant cells and delays tumor progression. These data suggest that the reduction of macrophage-mediated T cell exclusion increases tumor surveillance by CD8 T cells and renders tumors more responsive to anti-PD-1 treatment.
Copyright © 2018 the Author(s). Published by PNAS.