Currently approved viral vector-based and mRNA-based vaccine approaches against coronavirus disease 2019 (COVID-19) consider only homologous prime-boost vaccination. After reports of thromboembolic events, several European governments recommended using AstraZeneca’s ChAdOx1-nCov-19 (ChAd) only in individuals older than 60 years, leaving millions of already ChAd-primed individuals with the decision to receive either a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical School’s COVID-19 Contact Study cohort of healthcare professionals to monitor ChAd-primed immune responses before and 3 weeks after booster with ChAd (n = 32) or BioNTech/Pfizer’s BNT162b2 (n = 55). Although both vaccines boosted prime-induced immunity, BNT162b2 induced significantly higher frequencies of spike-specific CD4+ and CD8+ T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and P.1 variants of concern of severe acute respiratory syndrome coronavirus 2.
Mucosal vaccination via the respiratory tract can elicit protective immunity in animal infection models, but the underlying mechanisms are still poorly understood. We show that a single intranasal application of the replication-deficient modified vaccinia virus Ankara, which is widely used as a recombinant vaccination vector, results in prominent induction of bronchus-associated lymphoid tissue (BALT). Although initial peribronchiolar infiltrations, characterized by the presence of dendritic cells (DCs) and few lymphocytes, can be found 4 d after virus application, organized lymphoid structures with segregated B and T cell zones are first observed at day 8. After intratracheal application, in vitro–differentiated, antigen-loaded DCs rapidly migrate into preformed BALT and efficiently activate antigen-specific T cells, as revealed by two-photon microscopy. Furthermore, the lung-specific depletion of DCs in mice that express the diphtheria toxin receptor under the control of the CD11c promoter interferes with BALT maintenance. Collectively, these data identify BALT as tertiary lymphoid structures supporting the efficient priming of T cell responses directed against unrelated airborne antigens while crucially requiring DCs for its sustained presence.
The requirements for BALT formation are pathogen-dependent and, in the absence of FDC maturation, IL-17 can drive BALT formation via CXCL12 B cell recruitment.
T-cell development depends on recruitment of bone marrow-derived precursor cells to the thymus via a multistep adhesion cascade involving the chemokine receptor CCR9. However, CCR9 deficiency does not result in complete abrogation of progenitor entry into the adult thymus. Therefore, we tested the hypothesis that additional chemokine/ chemokine receptor systems might play a role in this process. To this end, we generated mice deficient in both CCR9 and CCR7. Deficiency in both chemokine receptors resulted in severely reduced numbers of early T-cell progenitors and in near-complete abrogation of thymus reconstitution. Progenitors in bone marrow and peripheral blood remained largely unaffected in CCR7 ؊/؊ CCR9 ؊/؊ mice, and direct intrathymic transfer of precursors from CCR7 ؊/؊ CCR9 ؊/؊ mice as well as single-mutant mice showed that intrathymic differentiation of these precursors remained functional. Thus, our data reveal a previously unrecognized role of CCR7 in progenitor seeding of the adult thymus, which is largely masked by compensatory effects of CCR9 signals. In turn, CCR7 signals can partially compensate for CCR9 signals, thus explaining the rather mild phenotype of CCR9 ؊/؊ mice with respect to progenitor seeding. (Blood. 2010;115:1906-1912
Neutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells via surface-expressed angiotensin-converting enzyme 2 (ACE2). We used a surrogate virus neutralization test (sVNT) and SARS-CoV-2 S protein-pseudotyped vesicular stomatitis virus (VSV) vector-based neutralization assay (pVNT) to assess the degree to which serum antibodies from coronavirus disease 2019 (COVID-19) convalescent patients interfere with the binding of SARS-CoV-2 S to ACE2. Both tests revealed neutralizing anti-SARS-CoV-2 S antibodies in the sera of ~90% of mildly and 100% of severely affected COVID-19 convalescent patients. Importantly, sVNT and pVNT results correlated strongly with each other and to the levels of anti-SARS-CoV-2 S1 IgG and IgA antibodies. Moreover, levels of neutralizing antibodies correlated with the duration and severity of clinical symptoms but not with patient age. Compared to pVNT, sVNT is less sophisticated and does not require any biosafety labs. Since this assay is also much faster and cheaper, sVNT will not only be important for evaluating the prevalence of neutralizing antibodies in a population but also for identifying promising plasma donors for successful passive antibody therapy.
Little is known about mechanisms determining the homeostasis of lymphocytes within lymphoid organs. Applying different mouse models, including conditionally proficient Ccr7 gene-targeted mice, we now show that semimature steady state dendritic cells (sDCs) constitutively trafficking into lymph nodes (LNs) were essential contributors to T cell homeostasis in these organs. sDCs provided vascular endothelial growth factor known to support high endothelial venule formation, thus facilitating enhanced homing of T cells to LNs. The presence of sDCs led to increased CCL21 production in T-zone fibroblastic reticular cells. CCL21 is a ligand for CCR7 known to regulate homing as well as retention of T cells in LNs. In addition, we provide evidence that CCL21 binds to the surface of DCs via its heparin-binding domain, further explaining why T cells leave LNs more rapidly in the absence of sDCs. Together, these data reveal multiple roles for sDCs in regulating T cell homeostasis in LNs.
Development of autoimmunity is a multi‐factorial process involving genetic predisposition as well as environmental and stochastic factors. Although the mechanisms responsible for the initiation of autoimmunity remain only partially understood, several studies have demonstrated that genetic predisposition plays a major role in this process. In the present study, we analyzed the influence of CCR7 signaling in the development of autoimmunity, because this chemokine receptor is essentially involved in the functional organization of thymus architecture. We demonstrate that CCR7‐deficient mice are prone to develop generalized multi‐organ autoimmunity. The autoimmune phenotype of CCR7–/– mice encompasses the presence of lymphocyte infiltrates in several peripheral organs, circulating autoantibodies against a multitude of tissue‐specific antigens and IgG deposition on renal glomeruli. Additionally, CCR7‐deficient mice show increased susceptibility to streptozotocin‐induced diabetes and spontaneously display signs of chronic autoimmune renal disease. Thus, this study identifies CCR7 as a genetic factor involved in the regulation of autoimmunity.
The chemokine receptor CCR7 has been implicated in maintenance of thymus morphology and establishment of tolerance to self-antigens. In this study, we provide direct evidence that negative selection of maturing thymocytes is defective in CCR7-deficent mice. Impaired negative selection was observed after TCR/CD3 complex stimulation in vivo as well as in vitro and was prominent in both doublepositive and semimature single positive cells (CD4 ؉ CD8 ؊ CD24 high ). It is noteworthy that thymocytes of CCR7 ؊/؊ mice display defective negative selection in response to endogenous superantigens, demonstrating that the defect also occurs under physiological conditions. Disturbed negative selection was correlated with delayed activation kinetics and decreased calcium flux response of CCR7 ؊/؊ thymocytes after in vitro TCR/CD3 stimulation, suggesting that an impaired response of CCR7 ؊/؊ thymocytes via TCR-mediated signaling is responsible for defective negative selection in these mice. IntroductionCCR7 is a major regulator of the immune system, orchestrating a broad spectrum of fundamental processes ranging from lymphoid organ development to induction of defensive immune responses as well as oral tolerance. [1][2][3] An important role for CCR7 in thymus compartmentalization and coordination of migratory events during thymopoiesis has been recently demonstrated. 4,5 Mice deficient in CCR7 or in its ligands CCL19 and CCL21-ser (plt/plt mice 6,7 ) display altered thymus architecture, impaired T-cell development, and decreased numbers of thymocytes. 4,5 Alterations of the thymus architecture are frequently observed in mice suffering from autoimmunity, such as mice deficient in the transcriptional regulator autoimmune regulator (Aire) and nonobese diabetic (NOD) mice. 8,9 In these strains, autoimmunity correlates with breakdown of central tolerance, although in NOD mice peripheral tolerance seems to be affected as well. [10][11][12] It has been noted previously that lack of CCR7 signaling is associated with the manifestation of autoimmunity to lachrymal and salivary glands. 13 Expanding this view, we recently demonstrated that CCR7-deficient mice in fact display a more generalized autoimmune phenotype affecting several organs. 14 These observations raised the possibility that CCR7-deficiency affects induction of central tolerance.The hallmark of central tolerance is the negative selection of potentially self-reactive thymocytes. This process guarantees the generation of a self-tolerant peripheral T-cell repertoire. The major mechanism of negative selection is clonal deletion. During this process, thymocytes reacting strongly to self-peptide-self-MHC complexes are eliminated. 15,16 Several studies using well characterized in vivo and in vitro models of negative selection suggest that clonal deletion can occur in all developmental stages of thymocytes, including double-negative, double-positive (DP), and singlepositive (SP). 15,[17][18][19][20] However, it is widely accepted that (for thymocytes expressing an MHC class II-restric...
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