The Emerging Role of HLA-E-Restricted CD8+ T Lymphocytes in the Adaptive Immune Response to Pathogens and Tumors

Human leukocyte antigen (HLA)-E is a nonclassical major histocompatibility complex (MHC) class I molecule of limited sequence variability that is expressed by most tissues albeit at low levels. HLA-E has been first described as the ligand of CD94/NKG2 receptors expressed mainly by natural killer (NK) cells, thus confining its role to the regulation of NK-cell function. However, recent evidences obtained by our and other groups indicate that HLA-E complexed with peptides can interact with αβ T-cell receptor (TCR) expressed on CD8+ T cells. Although, HLA-E displays a selective preference for nonameric peptides, derived from the leader sequence of various HLA class I alleles, several reports indicate that it can present also “noncanonical” peptides derived from both stress-related and pathogen-associated proteins. Because HLA-E displays binding specificity for innate CD94/NKG2 receptors, as well as all the features of an antigen-presenting molecule, its role in both natural and acquired immune responses has recently been re-evaluated

Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines

AbstractT-cell clones generated from both CD4+CD25+ and CD8+CD25+ human thymocytes were assessed for their ability to suppress the proliferative response to allogeneic stimulation of type 1 T-helper (Th1) or type 2 T-helper (Th2) clones derived from autologous CD4+CD25- thymocytes. Both CD4+ and CD8+ T-regulatory (Treg) cells completely suppressed the proliferation of Th1 clones but exhibited significantly lower suppressive activity on the proliferation of Th2 clones. The partial suppressive effect on Th2 cells was further reduced by the addition in culture of interleukin-4 (IL-4), whereas it was increased in the presence of an anti–IL-4 monoclonal antibody (mAb). The suppressive activity on Th2 clones was also completely inhibited by the addition of IL-7, IL-9, and IL-15 but not of IL-2, whereas the suppressive effect on Th1 clones was only reverted by the addition of IL-15. Of note, Th2 clones expressed significantly higher amounts of mRNA for IL-4 receptor (IL-4R) and IL-9R α chains than Th1 clones, whereas the expression of mRNA for IL-2R, IL-7R, and IL-15R α chains was comparable. Taken together, these findings demonstrate that Th2 cells have a lower susceptibility than Th1 cells to the suppressive activity of human CD25+ regulatory thymocytes, because they are able to produce, and to respond to, growth factors distinct from IL-2, such as IL-4 and IL-9. (Blood. 2004; 103:3117-3121

CXCR3 and α_Eβ₇ integrin identify a subset of CD8+ mature thymocytes that share phenotypic and functional properties with CD8+ gut intraepithelial lymphocytes

Background: We previously demonstrated the existence of two distinct subsets of T cell receptor (TCR)αβ+CD8αβ+ single positive (SP) cells in human postnatal thymus which express the chemokine receptor CCR7 or CXCR3 and migrate in vitro in response to their specific ligands. Aim: To investigate whether these two CD8+ thymocyte subsets had distinct peripheral colonisation. Methods: TCRαβ+CD8+ SP cells were obtained from normal postnatal thymus, mesenteric lymph node (LNs), small bowel, and peripheral blood (PB) specimens. Cells were then evaluated for expression of surface molecules, cytolytic potential, telomere length, and profile of cytokine production. Results: CD8+CCR7+CXCR3− thymocytes exhibited CD62L, in common with those which localise to LNs. In contrast, CD8+CCR7−CXCR3+ thymocytes lacked CD62L but exhibited CD103, similar to intraepithelial lymphocytes (IELs) present in the gut mucosa where the CXCR3 ligand, CXCL10, and the CD103 ligand, E-cadherin, are highly and consistently expressed. In addition, thymocytes and gut CD8+CXCR3+CD103+ cells showed comparable telomere length, which was higher than that of PB CXCR3+CD8+ T cells. However, both of these populations contained perforin and granzyme A, and displayed the ability to produce interferon γ and interleukin 2. Of note, CXCR3 deficient, in comparison with wild-type C57Black/6, mice showed decreased proportions of CD3+CD8αβ+ and increased proportions of CD3+CD8αα+ lymphocytes at gut level. Moreover, adoptive transfer of CD3+CD8αβ+ thymocytes from wild-type into CXCR3 deficient mice resulted in a significant increase in CD3+CD8αβ+ T cells in the gut mucosa but not in other tissues. Conclusions: The results of this study demonstrate the existence of a previously unrecognised subset of TCRαβ+CD8αβ+ SP CXCR3+CD103+ thymocytes which share phenotypic and functional features with CD8+ IELs, thus suggesting the possibility of their direct colonisation of the gut mucosa

Phenotypic and functional features of human Th17 cells

T helper (Th) 17 cells represent a novel subset of CD4+ T cells that are protective against extracellular microbes, but are responsible for autoimmune disorders in mice. However, their properties in humans are only partially known. We demonstrate the presence of Th17 cells, some of which produce both interleukin (IL)-17 and interferon (IFN)-γ (Th17/Th1), in the gut of patients with Crohn's disease. Both Th17 and Th17/Th1 clones showed selective expression of IL-23R, CCR6, and the transcription factor RORγt, and they exhibited similar functional features, such as the ability to help B cells, low cytotoxicity, and poor susceptibility to regulation by autologous regulatory T cells. Interestingly, these subsets also expressed the Th1-transcription factor T-bet, and stimulation of these cells in the presence of IL-12 down-regulated the expression of RORγt and the production of IL-17, but induced IFN-γ. These effects were partially inhibited in presence of IL-23. Similar receptor expression and functional capabilities were observed in freshly derived IL-17–producing peripheral blood and tonsillar CD4+ T cells. The demonstration of selective markers for human Th17 cells may help us to understand their pathogenic role. Moreover, the identification of a subset of cells sharing features of both Th1 and Th17, which can arise from the modulation of Th17 cells by IL-12, may raise new issues concerning developmental and/or functional relationships between Th17 and Th1

The emerging role of HLA-E-restricted CD8+ T lymphocytes in the adaptive immune response to pathogens and tumors

Human leukocyte antigen (HLA)-E is a nonclassical major histocompatibility complex (MHC) class I molecule of limited sequence variability that is expressed by most tissues albeit at low levels. HLA-E has been first described as the ligand of CD94/NKG2 receptors expressed mainly by natural killer (NK) cells, thus confining its role to the regulation of NK-cell function. However, recent evidences obtained by our and other groups indicate that HLA-E complexed with peptides can interact with αβ T-cell receptor (TCR) expressed on CD8 + T cells. Although, HLA-E displays a selective preference for nonameric peptides, derived from the leader sequence of various HLA class I alleles, several reports indicate that it can present also "noncanonical" peptides derived from both stress-related and pathogen-associated proteins. Because HLA-E displays binding specificity for innate CD94/NKG2 receptors, as well as all the features of an antigen-presenting molecule, its role in both natural and acquired immune responses has recently been re-evaluated

Ion dynamics and coherent structure formation following laser pulse self-channeling

The propagation of a superintense laser pulse in an underdense, inhomogeneous plasma has been studied numerically by two-dimensional particle-in-cell simulations on a time scale extending up to several picoseconds. The effects of the ion dynamics following the charge-displacement self-channeling of the laser pulse have been addressed. Radial ion acceleration leads to the ``breaking'' of the plasma channel walls, causing an inversion of the radial space-charge field and the filamentation of the laser pulse. At later times a number of long-lived, quasi-periodic field structures are observed and their dynamics is characterized with high resolution. Inside the plasma channel, a pattern of electric and magnetic fields resembling both soliton- and vortex-like structures is observed.Comment: 10 pages, 5 figures (visit http://www.df.unipi.it/~macchi to download a high-resolution version), to appear in Plasma Physics and Controlled Fusion (Dec. 2007), special issue containing invited papers from the 34th EPS Conference on Plasma Physics (Warsaw, July 2007

Mesenchymal stem cells are enriched in head neck squamous cell carcinoma, correlates with tumour size and inhibit T-cell proliferation

BACKGROUND: Cancer is a multifactorial disease not only restricted to transformed epithelium, but also involving cells of the immune system and cells of mesenchymal origin, particularly mesenchymal stem cells (MSCs). Mesenchymal stem cells contribute to blood- and lymph- neoangiogenesis, generate myofibroblasts, with pro-invasive activity and may suppress anti-tumour immunity. METHODS: In this paper, we evaluated the presence and features of MSCs isolated from human head neck squamous cell carcinoma (HNSCC). RESULTS: Fresh specimens of HNSCC showed higher proportions of CD90+ cells compared with normal tissue; these cells co-expressed CD29, CD105, and CD73, but not CD31, CD45, CD133, and human epithelial antigen similarly to bone marrow-derived MSCs (BM-MSCs). Adherent stromal cells isolated from tumour shared also differentiation potential with BM-MSCs, thus we named them as tumour-MSCs. Interestingly, tumour-MSCs showed a clear immunosuppressive activity on in vitro stimulated T lymphocytes, mainly mediated by indoelamine 2,3 dioxygenase activity, like BM-MSCs. To evaluate their possible role in tumour growth in vivo, we correlated tumour-MSC proportions with neoplasm size. Tumour-MSCs frequency directly correlated with tumour volume and inversely with the frequency of tumour-infiltrating leukocytes. CONCLUSIONS: These data support the concept that tumour-MSCs may favour tumour growth not only through their effect on stromal development, but also by inhibiting the anti-tumour immune response

Experimental Observation of the Thin-Shell Instability in a Collision-less Plasma

We report on the experimental observation of the instability of a plasma shell, which formed during the expansion of a laser-ablated plasma into a rarefied ambient medium. By means of a proton radiography technique, the evolution of the instability is temporally and spatially resolved on a timescale much shorter than the hydrodynamic one. The density of the thin shell exceeds that of the surrounding plasma, which lets electrons diffuse outward. An ambipolar electric field grows on both sides of the thin shell that is antiparallel to the density gradient. Ripples in the thin shell result in a spatially varying balance between the thermal pressure force mediated by this field and the ram pressure force that is exerted on it by the inflowing plasma. This mismatch amplifies the ripples by the same mechanism that drives the hydrodynamic nonlinear thin-shell instability (NTSI). Our results thus constitute the first experimental verification that the NTSI can develop in colliding flows.Funding agencies: EPSRC [EP/I031766/1, EP/K022415/1, EP/I029206/1, SFB-TR18, GRK1203, ENE2013-45661-C2-1-P, PEII-2014-008-P]; Vetenskapsradet [Dnr 2010-4063]; Triangle de la Physique RTRA network (ULIMAC)</p

Chitinase 3-like-1 is produced by human Th17 cells and correlates with the level of inflammation in juvenile idiopathic arthritis patients

Background: CHI3L1 is a chitinase-like protein without enzymatic activity, produced by activated macrophages, chondrocytes, neutrophils. Recent studies on arthritis, asthma, and inflammatory bowel diseases suggest that chitinases are important in inflammatory processes and tissue remodeling, but their production by human T cells, has never been reported. Methods: A microarray analysis of gene expression profile was performed on Th17 and classic Th1 cell clones and CHI3L1 was found among the up-regulated genes on Th17 cells. Different types of helper T cell clones (TCCs) were then evaluated by Real Time PCR (RT-PCR) for CHI3L1 mRNA expression; protein expression was investigated in cell lysates by western blotting and in cultures supernatants by ELISA. ELISA was also used to measure CHI3L1 in the serum and in the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients. Results: At mRNA level CHI3L1 was highly expressed by Th17, Th17/Th1, non classic Th1 and even in Th17/Th2 cell clones, whereas it was virtually absent in CD161- classic Th1 and Th2 TCCs. CHI3L1 was also detected in cell culture supernatants of Th17 and Th17-derived cells but not of classic Th1. Moreover CHI3L1 was higher in the SF than in serum of JIA patients, and it positively correlated with the frequency of Th17 and non-classic Th1 cells in SF. CHI3L1 in SF also positively correlated with the C reactive protein (CRP) serum levels, and with the levels of some proinflammatory cytokines, such as IL-6 and p40, which is the common subunit of IL12 and IL23. Conclusions: Here we describe for the first time CHI3L1 production by T cells owing the Th17 family. Moreover the positive correlation found between the frequency of Th17 and Th17-derived cell subsets and CHI3L1 levels in SF of JIA patients, in agreement with the suggested role of these cells in inflammatory process, candidates CHI3L1 as a possible biological target in JIA treatment