Crosstalk between T and B cells is crucial for generating high-affinity, class-switched antibody responses. The roles of CD4
+
T cells in this process have been well-characterised. In contrast, ...regulation of antibody responses by CD8
+
T cells is significantly less defined. CD8
+
T cells are principally recognised for eliciting cytotoxic responses in peripheral tissues and forming protective memory. However, recent findings have identified a novel population of effector CD8
+
T cells that co-opt a differentiation program characteristic of CD4
+
T follicular helper (Tfh) cells, upregulate the chemokine receptor CXCR5 and localise to B cell follicles. While it has been shown that CXCR5
+
CD8
+
T cells mediate the removal of viral reservoirs in the context of follicular-trophic viral infections and maintain the response to chronic insults by virtue of progenitor/stem-like properties, it is not known if CXCR5
+
CD8
+
T cells arise during acute peripheral challenges in the absence of follicular infection and whether they influence B cell responses
in vivo
in these settings. Using the ovalbumin-specific T cell receptor transgenic (OT-I) system in an adoptive transfer-immunisation/infection model, this study demonstrates that CXCR5
+
CD8
+
T cells arise in response to protein immunisation and peripheral viral infection, displaying a follicular-homing phenotype, expression of cell surface molecules associated with Tfh cells and limited cytotoxic potential. Furthermore, studies assessing the B cell response in the presence of OT-I or
Cxcr5
-/-
OT-I cells revealed that CXCR5
+
CD8
+
T cells shape the antibody response to protein immunisation and peripheral viral infection, promoting class switching to IgG2c in responding B cells. Overall, the results highlight a novel contribution of CD8
+
T cells to antibody responses, expanding the functionality of the adaptive immune system.
Abstract
Chimeric antigen receptor (CAR)-T cell immunotherapy is a novel treatment that genetically modifies the patients’ own T cells to target and kill malignant cells. However, identification of ...tumour-specific antigens expressed on multiple solid cancer types, remains a major challenge. P2X purinoceptor 7 (P2X7) is a cell surface expressed ATP gated cation channel, and a dysfunctional version of P2X7, named nfP2X7, has been identified on cancer cells from multiple tissues, while being undetectable on healthy cells. We present a prototype -human CAR-T construct targeting nfP2X7 showing potential antigen-specific cytotoxicity against twelve solid cancer types (breast, prostate, lung, colorectal, brain and skin). In xenograft mouse models of breast and prostate cancer, CAR-T cells targeting nfP2X7 exhibit robust anti-tumour efficacy. These data indicate that nfP2X7 is a suitable immunotherapy target because of its broad expression on human tumours. CAR-T cells targeting nfP2X7 have potential as a wide-spectrum cancer immunotherapy for solid tumours in humans.
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Type I regulatory (Tr1) cells are defined as FOXP3−IL-10-secreting clusters of differentiation (CD4+) T cells that contribute to immune suppression and typically express the markers ...LAG-3 and CD49b and other co-inhibitory receptors. These cells have not been studied in detail in the context of the resolution of acute infection in the lung. Here, we identify FOXP3- interleukin (IL)-10+ CD4+ T cells transiently accumulating in the lung parenchyma during resolution of the response to sublethal influenza A virus (IAV) infection in mice. These cells were dependent on IL-27Rα, which was required for timely recovery from IAV-induced weight loss. LAG-3 and CD49b were not generally co-expressed by FOXP3- IL-10+ CD4+ T cells in this model and four populations of these cells based on LAG-3 and CD49b co-expression were apparent LAG-3−CD49b− (double negative), LAG-3+CD49b+ (double positive), LAG-3+CD49b− (LAG-3+), LAG-3−CD49b+ (CD49b+). However, each population exhibited suppressive potential consistent with the definition of Tr1 cells. Notably, differences between these populations of Tr1 cells were apparent including differential dependence on IL-10 to mediate suppression and expression of markers indicative of different activation states and terminal differentiation. Sort-transfer experiments indicated that LAG-3+ Tr1 cells exhibited the capacity to convert to double negative and double positive Tr1 cells, indicative of plasticity between these populations. Together, these data determine the features and suppressive potential of Tr1 cells in the resolution of IAV infection and identify four populations delineated by LAG-3 and CD49b, which likely correspond to different Tr1 cell activation states.
Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly ...understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.
Identifying the molecular mechanisms that promote optimal immune responses to coronavirus disease 2019 (COVID-19) vaccination is critical for future rational vaccine design. Here, we longitudinally ...profile innate and adaptive immune responses in 102 adults after the first, second, and third doses of mRNA or adenovirus-vectored COVID-19 vaccines. Using a multi-omics approach, we identify key differences in the immune responses induced by ChAdOx1-S and BNT162b2 that correlate with antigen-specific antibody and T cell responses or vaccine reactogenicity. Unexpectedly, we observe that vaccination with ChAdOx1-S, but not BNT162b2, induces an adenoviral vector-specific memory response after the first dose, which correlates with the expression of proteins with roles in thrombosis with potential implications for thrombosis with thrombocytopenia syndrome (TTS), a rare but serious adverse event linked to adenovirus-vectored vaccines. The COVID-19 Vaccine Immune Responses Study thus represents a major resource that can be used to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.
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•Multi-omics profiling of responses in 102 adults after COVID-19 vaccination•Baseline and innate responses correlate with vaccine immunogenicity/reactogenicity•ChAdOx1-S, but not BNT162b2, induces an adenoviral memory response after the first dose•ChAdOx1-S memory response correlates with expression of pro-thrombotic proteins
Ryan et al. use a multi-omics approach to longitudinally profile innate and adaptive immune responses in blood collected from 102 adults at baseline and post-vaccination with the ChAdOx1-S, BNT162b2, or mRNA-1273 vaccines. The study reveals key differences in immune responses to adenovirus-vectored compared with mRNA COVID-19 vaccines.
Molecular plasmonics relies on the development of conductive nanostructures to yield large local electromagnetic enhancement enabling the detection of molecules located in their vicinity. Although ...various spectroscopic techniques benefit from such enhancement, performing different spectroscopic measurements on the same platform remains a challenge. As such, the rational design of structures capable of enhancement effects over a large spectral range, particularly from the visible to the mid-infrared, is of great interest. Herein, we have developed a series of metallic patterns, consisting of superimposed arrays of gold nanoprisms, that have the potential for surface-enhanced Raman spectroscopy (SERS), surface-enhanced fluorescence (SEF), and surface-enhanced infrared absorption (SEIRA). We first demonstrate that a modified version of the nanosphere lithography method can be used to fabricate such platforms. Patterns with selected sizes can further be produced by electron-beam lithography with virtually no defects, thus yielding tunable and precise optical resonances from the visible to the mid-infrared range. The hexagonal lattices were composed of smaller prisms (0.25 μm prism base length) incorporated for SERS and SEF applications and larger triangles (1–2 μm base size) for SEIRA purposes. The superimposed patterns display regions that are compatible with SEF, SERS, and SEIRA, thus opening promising applications for multispectral detection of molecules.
Purpose To address gaps in understanding and treating lower urinary tract symptoms, the NIDDK created the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN). The goals of LURN are to ...work collaboratively to 1) identify and explain the important subtypes of lower urinary tract symptoms; 2) improve the measurement of patient experiences of lower urinary tract symptoms; 3) disseminate novel findings to researchers, clinicians and patients; and 4) generate data, research tools and biological samples for future studies. Materials and Methods As a first step in understanding subtypes of lower urinary tract symptoms, LURN will focus on disorders of urinary sensation (eg urgency) and their causes. These are being examined with respect to patient experience, organism or systemic factors, genitourinary organs and tissues, and cellular/molecular factors. This is being achieved via an observational cohort study that is currently enrolling patients with lower urinary tract symptoms (target number 1,000) and that will extensively characterize patients with lower urinary tract symptoms. Future studies embedded within the observational cohort study will focus on neuroimaging and sensory testing, biomarkers and organ based factors. To advance the science of measurement of lower urinary tract symptoms, LURN is also developing and evaluating a comprehensive set of self-report questions to provide more granular assessments of lower urinary tract symptoms. Results The LURN has taken its first steps by developing a framework for studying lower urinary tract symptom subtypes. Conclusions In developing this framework, the LURN is choosing an initial domain on which to focus (sensory experiences), and creating and executing protocols designed to improve measurement of self-reported symptoms and identifying patient subtypes.
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