Patients with immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis and inflammatory bowel disease, are at increased risk of infection. International guidelines recommend ...vaccination to limit this risk of infection, although live attenuated vaccines are contraindicated once immunosuppressive therapy has begun. Biologic therapies used to treat IMIDs target the immune system to stop chronic pathogenic process but may also attenuate the protective immune response to vaccines. Here, we review the current knowledge regarding vaccine responses in IMID patients receiving treatment with biologic therapies, with a focus on the interleukin (IL)-12/23 inhibitors. B cell-depleting therapies, such as rituximab, strongly impair vaccines immunogenicity, and tumor necrosis factor (TNF) inhibitors and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) fusion protein abatacept are also associated with attenuated antibody responses, which are further diminished in patients taking concomitant immunosuppressants. On the other hand, integrin, IL-6, IL-12/23, IL-17, and B-cell activating factor (BAFF) inhibitors do not appear to affect the immune response to several vaccines evaluated. Importantly, treatment with biologic therapies in IMID patients is not associated with an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or developing severe disease. However, the efficacy of SARS-CoV-2 vaccines on IMID patients may be reduced compared with healthy individuals. The impact of biologic therapies on the response to SARS-CoV-2 vaccines seems to replicate what has been described for other vaccines. SARS-CoV-2 vaccination appears to be safe and well tolerated in IMID patients. Attenuated but, in general, still protective responses to SARS-CoV-2 vaccination in the context of certain therapies warrant current recommendations for a third primary dose in IMID patients treated with immunosuppressive drugs.
Objectives
A fundamental question in influenza research is whether antibody titre decline upon successive exposure to variant strains is consequent to recall of cross‐reactive memory B cells that ...competitively inhibit naive B‐cell responses. In connection, it is not clear whether naive and memory B cells remain phenotypically distinct acutely after activation such that they may be distinguished ex vivo.
Methods
Here, we first compared the capacity of anti‐Ig and Toll‐like‐receptor (TLR) 7/8 and TLR9 agonists (R848 and CpG) to augment human B‐cell differentiation induced by IL‐21 and sCD40L. The conditions that induced optimal differentiation were then used to compare the post‐activation phenotype of sort‐purified naive and memory B‐cell subsets by FACS and antibody‐secreting cell (ASC) ELISPOT.
Results
Sort‐purified naive and memory B cells underwent robust plasmablast and ASC formation when stimulated with R848, but not CpG, and co‐cultured with monocytes. This coincided with increased IL‐1β and IL‐6 production when B cells were co‐cultured with monocytes and stimulated with R848, but not CpG. Naive B cells underwent equivalent ASC generation, but exhibited less class‐switch and modulation of CD27, CD38 and CD20 expression than memory B cells after stimulation with R848 and monocytes for 6 days.
Conclusion
Stimulation with R848, IL‐21 and sCD40L in the presence of monocytes induces robust differentiation and ASC generation from both naive and memory B‐cells. However, naive and memory B cells retain key phenotypic differences after activation that may facilitate ex vivo discrimination and better characterisation of acute responses to variant antigens.
This study contrasts the requirements and outcomes of human B‐cell subset differentiation in vitro. R848 induced more potent B‐cell differentiation than CpG when combined with sCD40L and IL‐21, an effect that was mediated via monocyte activation by R848 but not by CpG. Naive and memory B cells retained key phenotypic differences after activation that may facilitate ex vivo discrimination and better characterisation of acute responses to variant antigens.
Altered B‐cell homeostasis underlies a wide range of pathologies, from cancers to autoimmunity and immunodeficiency. The molecular safeguards against those disorders, which also allow effective ...immune responses, are therefore particularly critical. Here, we review recent findings detailing the fine control of B‐cell homeostasis, during B‐cell development, maturation in the periphery and during activation and differentiation into antibody‐producing cells.
Altered B‐cell homeostasis underlies a wide range of pathologies, from cancers, to autoimmunity, and immunodeficiency. The molecular safeguards against those malignancies, which also allow effective immune responses, are therefore particularly critical. Here, we review recent findings detailing the fine control of B‐cell homeostasis, during B‐cell development, maturation in the periphery and during activation and differentiation into antibody‐producing cells.
Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune ...encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.
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•Gut-derived IgA+ plasma cells (PC) access extra-intestinal tissues in the steady state•Gut-derived IgA+ PC access the CNS during EAE and attenuate disease•IgA+ PC attenuate EAE in an IL-10-dependent manner•An IgA-promoting protist and BAFF overexpression both confer resistance to EAE
Immune cells can travel from the gut to the brain to suppress neuroinflammation in a mouse model of multiple sclerosis.
Activation of the T cell receptor (TCR) by antigen is the key step in adaptive immunity. In the αβTCR, antigen induces a conformational change at the CD3 subunits (CD3 CC) that is absolutely required ...for αβTCR activation. Here, we demonstrate that the CD3 CC is not induced by antigen stimulation of the mouse G8 or the human Vγ9Vδ2 γδTCR. We find that there is a fundamental difference between the activation mechanisms of the αβTCR and γδTCR that map to the constant regions of the TCRαβ/γδ heterodimers. Enforced induction of CD3 CC with a less commonly used monoclonal anti-CD3 promoted proximal γδTCR signaling but inhibited cytokine secretion. Utilizing this knowledge, we could dramatically improve in vitro tumor cell lysis by activated human γδ T cells. Thus, manipulation of the CD3 CC might be exploited to improve clinical γδ T cell-based immunotherapies.
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•There is a fundamental difference between αβTCR and γδTCR activation mechanisms•Antigens do not trigger the CD3 conformational change in the γδTCR•The CD3 conformational change promotes proximal signaling events in γδ T cells•Enforced induction of CD3 CC greatly enhances tumor cell killing by γδ T cells
In this study, Dopfer et al. show that, in sharp contrast to αβTCRs, γδTCRs do not undergo the CD3 conformational change for γδ T cell proliferation or cytokine production.
The human αβ T-cell receptor (TCR) is composed of a variable heterodimer (TCRαβ) and three invariant dimers (CD3γε, CD3δε, and ζζ/CD247
2
). The role of each invariant chain in the stepwise ...interactions among TCR chains along the assembly is still not fully understood. Despite the high sequence homology between CD3γ and CD3δ, the clinical consequences of the corresponding immunodeficiencies (ID) in humans are very different (mild and severe, respectively), and mouse models do not recapitulate findings in human ID. To try to understand such disparities, we stably knocked down (KD)
CD3D
or
CD3G
expression in the human Jurkat T-cell line and analyzed comparatively their impact on TCRαβ assembly, transport, and surface expression. The results indicated that TCR ensembles were less stable and CD3ε levels were lower when CD3γ, rather than CD3δ, was scarce. However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD247
2
, and barely reached the T-cell surface (<11% of normal controls) in any of the
CD3
KD cells. This is in sharp contrast to human CD3γ ID, whose mature T cells express higher levels of surface TCR (>30% vs. normal controls).
CD3
KD of human T-cell progenitors followed by mouse fetal thymus organ cultures showed high plasticity in emerging immature polyclonal T lymphocytes that allowed for the expression of significant TCR levels which may then signal for survival in CD3γ, but not in CD3δ deficiency, and explain the immunological and clinical disparities of such ID cases.
Chronic Lymphocytic Leukemia (CLL) is characterized by the expansion of CD19
CD5
B cells but its origin remains debated. Mutated CLL may originate from post-germinal center B cells and unmutated CLL ...from CD5
mature B cell precursors. Irrespective of precursor types, events initiating CLL remain unknown. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation remains unclear.
We generated novel CLL models lacking BAFF or APRIL.
experiments were conducted to explore the impact of BAFF or APRIL loss on leukemia initiation, progression, and dissemination. Additionally, RNA-seq and quantitative real-time PCR were performed to unveil the transcriptomic signature influenced by BAFF in CLL. The direct role of BAFF in controlling the expression of tumor-promoting genes was further assessed in patient-derived primary CLL cells
.
Our findings demonstrate a crucial role for BAFF, but not APRIL, in the initiation and dissemination of CLL cells. In the absence of BAFF or its receptor BAFF-R, the TCL1 transgene only increases CLL cell numbers in the peritoneal cavity, without dissemination into the periphery. While BAFF binding to BAFF-R is dispensable for peritoneal CLL cell survival, it is necessary to activate a tumor-promoting gene program, potentially linked to CLL initiation and progression. This direct role of BAFF in controlling the expression of tumor-promoting genes was confirmed in patient-derived primary CLL cells ex-vivo.
Our study, involving both mouse and human CLL cells, suggests that BAFF might initiate CLL through mechanisms independent of cell survival. Combining current CLL therapies with BAFF inhibition could offer a dual benefit by reducing peripheral tumor burden and suppressing transformed CLL cell output.
The CD3 subunits of the T-cell antigen receptor (TCR) play a central role in regulation of surface TCR expression levels. Humans who lack CD3γ (γ
—
) show reduced surface TCR expression levels and ...abolished phorbol ester (PMA)-induced TCR down-regulation. The response to PMA is mediated by a double leucine motif in the intracellular (IC) domain of CD3γ. However, the molecular cause of the reduced TCR surface expression in γ
—
lymphocytes is still not known. We used retroviral vectors carrying wild type CD3γ or CD3δ or the following chimeras (EC-extracellular, TM-transmembrane and IC): δ
EC
γ
TM
γ
IC
(δγγ for short), γγδ, γδδ and γγ-. Expression of γγγ, γγδ, γδδ or γγ- in the γ
—
T cell line JGN, which lacks surface TCR, demonstrated that cell surface TCR levels in JGN were dependent on the EC domain of CD3γ and could not be replaced by the one of CD3δ. In JGN and primary γ
—
patient T cells, the tested chimeras confirmed that the response to PMA maps to the IC domain of CD3γ. Since protein homology explains these results better than domain structure, we conclude that CD3γ contributes conformational cues that improve surface TCR expression, likely at the assembly or membrane transport steps. In JGN cells all chimeric TCRs were signalling competent. However, an IC domain at CD3γ was required for TCR-induced IL-2 and TNF-α production and CD69 expression, indicating that a TCR without a CD3γ IC domain has altered signalling capabilities.
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