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:AIM: To investigate the adaptive properties of NK cells, by comparing the expression profiles of FACS-sorted KIR+ (CD158b1b2j) and KIR- NK cells from patients experiencing or not a Cytomegalovirus (HCMV) reactivation after haploidentical hematopoietic stem cell transplantation (h-HSCT). RESULTS: Our flow cytometry data demonstrate that KIR+ NK cells are expanded in h-HSCT patients upon HCMV reactivation, thus suggesting that these cells could be important in controlling the viral infection and could be endowed with adaptive features. By comparing the expression profiles of KIR+ and KIR- NK cells from reacivated patients, we demonstrated a cytokine receptor unbalance, a prevalence of pathways associated to mitochondrial respiration and consequent ATP synthesis, a downregulation of genes involved in epigenetic reprogramming, all properties attributable adaptive NK cells. By comparing the molecular fingerprint of KIR+ NK cells between patients experiencing a HCMV reactivation and not reactivated patients, we observed in reactivated group an upregulation of INFG expression and in genes involved in Signaling receptor activity and MHC class II antigen presentation , thus strengthens the hypothesis that our KIR+ NK cells in reactevated h-HSCT patients are able to produce IFN-γ driving specific responses upon re-stimulation. However, the enrichment in PD-1 signaling, let us speculate that KIR+ NK cells from reactivated h-HSCT patients have impaired effector-functions.
Project description:Purpose: To characterize the tumor-specific TRM cells in LNs, skin, lung and liver in mice with melanoma-associated vitiligo (MAV). Bulk RNA-seq was performed to identify populations of CD8 T cells with TRM transcriptional characteristics. Methods: CD8+THy1.1+ T cells were sorted from DLN, skin lung and liver of MAV mice and bulk RNA-sequenced Results: Heterogenouse CD8 memory populations with both circulatating and resident phenotypes were identified. Conclusions: Tumor-specific CD8 T cells form TRM responses in tumor-draining LNs.