BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4+ Tcell responses to persistent antigen.
Soon after activation, CD4+ Tcells are segregated into BCL6+ follicular helper (Tfh) and BCL6- effector (Teff) Tcells. Here, we explored how these subsets are maintained during chronic antigen stimulation using the mouse chronic LCMV infection model. Using single cell-transcriptomic and epigenomic analyses, we identified a population of PD-1+ TCF-1+ CD4+ Tcells with memory-like features. TCR clonal tracing and adoptive transfer experiments demonstrated that these cells have self-renewal capacity and continue to give rise to both Teff and Tfh cells, thus functioning as progenitor cells. Conditional deletion experiments showed Bcl6-dependent development of these progenitors, which were essential for sustaining antigen-specific CD4+ Tcell responses to chronic infection. An analogous CD4+ Tcell population developed in draining lymph nodes in response to tumors. Our study reveals the heterogeneity and plasticity of CD4+ Tcells during persistent antigen exposure and highlights their population dynamics through a stable, bipotent intermediate state.
View details for DOI 10.1016/j.immuni.2022.05.003
View details for PubMedID 35637103
KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.
Science (New York, N.Y.)
Here we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from celiac disease patients' leukocytes in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, which correlated with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity post infection. Our results indicate that in both species, these regulatory CD8+ T cells act uniquely to suppress pathogenic T cells in autoimmune and infectious diseases.
View details for DOI 10.1126/science.abi9591
View details for PubMedID 35258337
Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma.
The Journal of clinical investigation
2021; 131 (20)
Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote "off-the-shelf" precision immunotherapies, alleviating limitations of personalized treatments.
View details for DOI 10.1172/JCI129466
View details for PubMedID 34651586
High-throughput and single-cell T cell receptor sequencing technologies.
T cells express T cell receptors (TCRs) composed of somatically recombined TCRalpha and TCRbeta chains, which mediate recognition of major histocompatibility complex (MHC)-antigen complexes and drive the antigen-specific adaptive immune response to pathogens and cancer. The TCR repertoire in each individual is highly diverse, which allows for recognition of a wide array of foreign antigens, but also presents a challenge in analyzing this response using conventional methods. Recent studies have developed high-throughput sequencing technologies to identify TCR sequences, analyze their antigen specificities using experimental and computational tools, and pair TCRs with transcriptional and epigenetic cell state phenotypes in single cells. In this Review, we highlight these technological advances and describe how they have been applied to discover fundamental insights into T cell-mediated immunity.
View details for DOI 10.1038/s41592-021-01201-8
View details for PubMedID 34282327
Identification of presented SARS-CoV-2 HLA class I and HLA class II peptides using HLA peptidomics.
The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. As viruses evolve by acquiring mutations, it is essential to identify a range of presented viral antigens. Using HLA peptidomics, we are able to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides presented by highly prevalent HLA class I (HLA-I) molecules by using infected cells as well as overexpression of SARS-CoV-2 genes. We find 26 HLA-I peptides and 36 HLA class II (HLA-II) peptides. Among the identified peptides, some are shared between different cells and some are derived from out-of-frame open reading frames (ORFs). Seven of these peptides were previously shown to be immunogenic, and we identify two additional immunoreactive peptides by using HLA multimer staining. These results may aid the development of the next generation of SARS-CoV-2 vaccines based on presented viral-specific antigens that span several of the viral genes.
View details for DOI 10.1016/j.celrep.2021.109305
View details for PubMedID 34166618
The Power of Single Cell Technologies; from T Cell Receptor to Antigen(s) in Multiple Sclerosis
WILEY. 2020: S198
View details for Web of Science ID 000572509100353