T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,015 samples (from 827 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 83.8% [95% CI = 77.6-89.4]; Day 8-14 = 92.4% [87.6-96.6]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 96.7% [93.0-99.2]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in vaccine development as well as clinical diagnostics and monitoring.
Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.c g
SEN virus (SEN-VAfter cloning of the hepatitis C virus (HCV) 1 and development of sensitive serologic and molecular assays for this pathogen, a dramatic decline in the incidence of transfusionassociated hepatitis occurred. 2,3 However, approximately 10% of transfusion-associated hepatitis cases 4 and 20% of community-acquired hepatitis cases 5 do not have a defined etiology suggesting the existence of additional causative agents. Hepatitis G virus (HGV), 6 also known as GB virus C (GBV-C), 7 was initially suggested as a causative agent of non-A to E hepatitis, but this was not confirmed in further studies. [8][9][10] The originally described TT virus (TTV), discovered in 1997 by representational difference analysis, was detected in 3 of 5 cases of transfusion-associated hepatitis and was proposed as a potential cause of non-A to E hepatitis. 11 Using TTV primers identical to those reported, non-A to E hepatitis cases and controls in the NIH prospective series were tested but no association with transfusion-associated hepatitis was found. 12 Subsequently, primers to more conserved regions of the TTV genome were used in studies in Japan, and the agent was found in greater than 90% of Japanese blood donors. 13 This further diminished the likelihood that TTV was the cause of transfusion-associated hepatitis and precluded the possibility of a practical screening assay. Other studies have also confirmed the high prevalence of TTV and its lack of association with transfusion-associated hepatitis. 14,15 Recently, a novel DNA virus designated SEN virus (SEN-V) was discovered in the serum of an intravenous drug abuser also infected with human immunodeficiency virus. 16,17 SEN-V was initially described as a single-stranded DNA virus of approximately 3,800 nucleotides. 16 Phylogenetic analysis of SEN-V has shown the existence of 8 strains. 18 Although structurally similar to TTV, SEN-V has less than 55% sequence homology and less than 37% amino acid homology with the TTV prototype. 18 Preliminary studies of SEN-V variants were conducted by Dr. Primi (DiaSorin Inc., Brescia, Italy). The prevalence of 5 SEN-V strains (A, B, H [former C], D, and E) and a consensus sequence designated total SEN-V were measured in various donor and patient populations. It was shown that measuring total SEN-V was not practical because the prevalence in donors was 13% and the rate in all transfused populations exceeded 70%. SENV-B was also excluded as a useful screening assay because it was present in 10% of donors and only 8% of patients with transfusion-associated non-A to E hepatitis. SENV-A and SENV-E were found in low prevalence in donors, but did not appear to be associated with non-A to E hepatitis. In contrast, SENV-D and SENV-H had favorable prevalence ratios being found in less than 1% of donors and more than 50% of transfusion-associated non-A to E cases. These initial polymerase chain reaction (PCR) data were confirmed by cloning and sequencing which showed that SENV-D and SENV-H sequences were found in a high proportion of non-A to E ...
Combination of chemotherapy and immunotherapy to increase the effectiveness of an antitumor immune response is currently regarded as an attractive antitumor strategy. In a pilot clinical trial, we have recently documented an increase of melanoma antigen A (Melan-A)-specific, tumor-reactive, long-lasting effectormemory CD8 + T cells after the administration of dacarbazine (DTIC) 1 day before peptide vaccination in melanoma patients. Global transcriptional analysis revealed a DTIC-induced activation of genes involved in the immune response and leukocyte activation. To identify the possible mechanisms underlying this improved immune response, we have compared the endogenous and the treatment-induced anti-Melan-A response at the clonal level in patients treated with the vaccine alone or with DTIC plus vaccine. We report a progressive widening of T-cell receptor (TCR) repertoire diversity, accompanied by high avidity and tumor reactivity, only in Melan-A-specific T-cell clones of patients treated with chemoimmunotherapy, with a trend toward longer survival. Differently, patients treated with vaccine alone showed a tendency to narrowing the TCR repertoire diversity, accompanied by a decrease of tumor lytic activity in one patient. Collectively, our findings indicate that DTIC plus vaccination shapes the TCR repertoire in terms of diversity and antitumor response, suggesting that this combined therapy could be effective in preventing melanoma relapse. Cancer Res; 70(18); 7084-92. ©2010 AACR.
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