Antigen Processing and Remodeling of the Endosomal Pathway: Requirements for Antigen Cross-Presentation

Cross-presentation of endocytosed antigen as peptide/class I major histocompatibility complex complexes plays a central role in the elicitation of CD8+ T cell clones that mediate anti-viral and anti-tumor immune responses. While it has been clear that there are specific subsets of professional antigen presenting cells capable of antigen cross-presentation, identification of mechanisms involved is still ongoing. Especially amongst dendritic cells (DC), there are specialized subsets that are highly proficient at antigen cross-presentation. We here present a focused survey on the cell biological processes in the endosomal pathway that support antigen cross-presentation. This review highlights DC-intrinsic mechanisms that facilitate the cross-presentation of endocytosed antigen, including receptor-mediated uptake, maturation-induced endosomal sorting of membrane proteins, dynamic remodeling of endosomal structures and cell surface-directed endosomal trafficking. We will conclude with the description of pathogen-induced deviation of endosomal processing, and discuss how immune evasion strategies pertaining endosomal trafficking may preclude antigen cross-presentation

Neutrophilia, lymphopenia and myeloid dysfunction: A living review of the quantitative changes to innate and adaptive immune cells which define COVID-19 pathology

Destabilisation of balanced immune cell numbers and frequencies is a common feature of viral infections. This occurs due to, and further enhances, viral immune evasion and survival. Since the discovery of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which manifests in coronavirus disease 2019 (COVID-19), a great number of studies have described the association between this virus and pathologically increased or decreased immune cell counts. In this review, we consider the absolute and relative changes to innate and adaptive immune cell numbers, in COVID-19. In severe disease particularly, neutrophils are increased, which can lead to inflammation and tissue damage. Dysregulation of other granulocytes, basophils, and eosinophils represent an unusual COVID-19 phenomenon. Contrastingly, the impact on the different types of monocytes leans more strongly to an altered phenotype, e.g. HLA-DR expression, rather than numerical changes. However, it is the adaptive immune response which bears the most profound impact of SARS-CoV-2 infection. T cell lymphopenia correlates with increased risk of ICU admission and death; therefore, this parameter is particularly important for clinical decision making. Mild and severe disease differ in the rate of immune cell counts returning to normal levels post disease. Tracking the recovery trajectories of various immune cell counts may also have implications for long-term COVID-19 monitoring. This review represents a snapshot of our current knowledge, showing that much has been achieved in a short period of time. Alterations in counts of distinct immune cells represent an accessible metric to inform patient care decision or predict disease outcomes

Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia

Antiplatelet-antibody-producing B cells play a key role immune thrombocytopenia (ITP) pathogenesis; however, little is known about T-cell dysregulations that support B-cell differentiation. During the past decade, T follicular helper cells (TFHs) have been characterized as the main T-cell subset within secondary lymphoid organs that promotes B-cell differentiation leading to antibody class-switch recombination and secretion. Herein, we characterized TFHs within the spleen of 8 controls and 13 ITP patients. We show that human splenic TFHs are the main producers of interleukin (IL)-21, express CD40 ligand(CD154), and are located within the germinal center of secondary follicles. Compared with controls, splenic TFH frequency is higher in ITP patients and correlates with germinal center and plasma cell percentages that are also increased. In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients. Overall, these results point out the involvement of TFH in ITP pathophysiology and the potential interest of IL-21 and CD40 as therapeutic targets in ITP

T cell phenotypes in COVID-19 - a living review

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients’ long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation

The role and uses of antibodies in COVID-19 infections: a living review

Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity

Editorial: Regulatory Mechanisms of Early Intracellular Signaling in T Lymphocytes

EA was funded by the Consejería de Salud de Andalucía, Junta de Andalucía (Grant PI-0055-2017 to EA), and Fundación Biomédica Cádiz Proyectos INIBICA 2019 (Grant LI19/I14NCO15). EBC was supported by John Fell Fund, and ERC AdG 670930 to Michael Dustin. AM was funded by the Leading Research Groups Support project obtained in 2019 (with the subsidy, increased for the period 2020–2025 in the amount of 2% of the subsidy referred to Art. 387 (3) of the Law of 20 July 2018 on Higher Education and Science, Poland).Ye

Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis

Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment, but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor mitochondrial A (TFAM). TFAM, whilst also necessary for normal B cell development, is required for entry of activated GC-precursor B cells into the germinal center reaction, and deletion of Tfam significantly impairs GC formation, function, and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation, and deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacologic inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells, and induces similar defects in the actin cytoskeleton