Project description:Previous reports show that Ly49+CD8+ T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8+ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalents of the Ly49 family, in the blood and inflamed tissues of various human autoimmune diseases. Moreover, KIR+CD8+ T cells can efficiently eliminate pathogenic gliadin-specific CD4+ T cells from Celiac disease (CeD) patients’ leukocytes in vitro. Furthermore, we observe elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 and influenza-infected patients, and correlate with disease severity and vasculitis in COVID-19. Expanded KIR+CD8+ T cells from these different diseases display shared phenotypes and similar T cell receptor sequences. These results characterize a regulatory CD8+ T cell subset in humans, broadly active in both autoimmune and infectious diseases, which we hypothesize functions to control self-reactive or otherwise pathogenic T cells.
Project description:We studied the heterogeneity among human KIR/NKG2A+CD8+ T cells. First, we found that KIRs and NKG2A are expressed on human CD8+ T cells in a mutually exclusive manner. Therefore, we compared KIR+CD8+ and NKG2A+CD8+ T cells in regards to TCR overlap and transcriptomic profiles and demonstrated that KIR+CD8+ and NKG2A+CD8+ T cells are distinct innate-like populations.
Project description:KIR+ CD8 T cells (Live CD3+CD56-TCRab+CD8+KIR+ cells) were sorted from the blood of healthy subjects (N=10) and patients with MS (N=2), SLE (N=6), or CeD (N=5) and subjected to single-cell RNA-seq analysis by Smart-seq2. In parallel, we also analyzed their T-cell receptor (TCR) α and β sequences. Unsupervised clustering of these KIR+CD8+ T cells by Seurat identified six clusters, with Clusters 1 to 3 mostly containing expanded KIR+CD8+ T cells (≥2 cells expressing same TCR) and Clusters 5 and 6 consisting of unexpanded cells expressing unique TCRs. There are common features shared by KIR+CD8+ T cells from healthy subjects and different diseases, yet there is also heterogeneity (i.e., upregulated type I IFN signaling and glycolysis in Clusters 2 and 3) associated with different diseases or treatments.
Project description:Uterine NK cells (uNK cells) form a distinct immune cell population in the endometrium and decidua. Here, we FACS-sorted KIR-CD39-,KIR+CD39- and KIR+CD39+ uNK cells from decidual samples.
Project description:Severe respiratory viral infectious diseases such as influenza and COVID- 19 espe-cially affect the older population. This is partly ascribed to diminished CD8+ T- cell re-sponses a result of aging. The phenotypical diversity of the CD8+ T- cell population has made it difficult to identify the impact of aging on CD8+ T- cell subsets associated with diminished CD8+ T- cell responses. Here we identify a novel human CD8+ T- cell subset characterized by expression of Killer- cell Immunoglobulin-l ike Receptors (KIR+) and CD45RA (RA+). These KIR+RA+ T cells accumulated with age in the blood of healthy individuals (20– 82 years of age, n = 50), expressed high levels of aging- related mark-ers of T- cell regulation, and were functionally capable of suppressing proliferation of other CD8+ T cells. Moreover, KIR+RA+ T cells were a major T- cell subset becoming activated in older adults suffering from an acute respiratory viral infection (n = 36), including coronavirus and influenza virus infection. In addition, older adults with influ-enza A infection showed that higher activation status of their KIR+RA+ T cells associ-ated with longer duration of respiratory symptoms. Together, our data indicate that KIR+RA+ T cells are a unique human T- cell subset with regulatory properties that may explain susceptibility to viral respiratory disease at old age.
Project description:We have performed whole genome expression arrays covering over 47000 transcripts comparing the transcriptional profile of NKp80+ to NKp80- CD8+ CCR7- alpha beta T cells. A highly similar global gene expression profile was observed between both memory phenotype T cell subsets. Interestingly, the majority of differentially expressed genes are immune-associated. NKp80+ cells contained markedly increased levels of transcripts encoding for MHC class I and II molecules and for numerous members of the KIR family. Also other NK-related transcripts were more abundantly expressed in the NKp80+ subset. With regards to cytokines, chemokines and their receptors, transcripts important for homeostasis and proliferation are expressed differently. Also transcripts encoding for adhesion molecules are present at different levels in both T cell subsets. Further cytotoxic effector molecules are expressed differently. Experiment Overall Design: We used CD4, CD14 depleted PBMCs pooled from six healthy donors. Following FACS sorting of NKp80+ CD8+ CCR7- alpha beta T cells and NKp80- cells, respectively, transcript levels of both subsets have been compared on human whole genome expression arrays.