Intrahepatic and peripheral blood phenotypes of natural killer and T cells: differential surface expression of killer cell immunoglobulin-like receptors.

Deep characterization of the frequencies, phenotypes and functionalities of liver and peripheral blood natural killer (NK), natural killer T (NKT) and T cells from healthy individuals is an essential step to further interpret changes in liver diseases. These data indicate that CCR7, a chemokine essential for cell migration through lymphoid organs, is almost absent in liver NK and T cells. CD56bright NK cells, which represent half of liver NK cells, showed lower expression of the inhibitory molecule NKG2A and an increased frequency of the activation marker NKp44. By contrast, a decrease of CD16 expression with a potential decreased capacity to perform antibody-dependent cellular cytotoxicity was the main difference between liver and peripheral blood CD56dim NK cells. Liver T cells with an effector memory or terminally differentiated phenotype showed an increased frequency of MAIT cells,T-cell receptor-γδ (TCR-γδ) T cells and TCR-αß CD8+ cells, with few naive T cells. Most liver NK and T cells expressed the homing markers CD161 and CD244. Liver T cells revealed a unique expression pattern of killer cell immunoglobulin-like receptors (KIR) receptors, with increased degranulation ability and higher secretion of interferon-γ. Hence, the liver possesses a large amount of memory and terminally differentiated CD8+ cells with a unique expression pattern of KIR activating receptors that have a potent functional capacity as well as a reduced amount of CCR7, which are unable to migrate to regional lymph nodes. These results are consistent with previous studies showing that liver T (and also NK) cells likely remain and die in the liver.

Evaluation of paternal lymphocyte immunotherapy and potential biomarker mixed lymphocyte reaction-blocking factor in an Argentinian cohort of women with unexplained recurrent spontaneous abortion and unexplained infertility.

PROBLEM: Analyze the effect of paternal immunotherapy treatment (PIT) in primary and secondary unexplained recurrent spontaneous abortion (URSA) and unexplained infertility (UI). METHODS OF STUDY: A retrospective study analyzed a two-year follow-up between the generation of MLR-Bfs after PIT treatment (or controls first consultation) and a live birth. Recruited patients included primary URSA with two or more miscarriages at <12 weeks gestation, secondary URSA with previous live birth before two or more miscarriages, and UI with inability to conceive after 2 years of regular unprotected intercourse or in vitro fertilizations (IVF). PIT treated were compared with untreated controls. RESULTS: Primary URSA: live birth was 241/416 (58%) versus 64/282 (23%) controls (p < .0001). Up to age 35, success was 158/217 (73%) and 37/144 (26%) controls (p < .0001). With 3 or more previous URSA, success was 90/135 (67%) versus 17/79 (22%) controls (p < .0001). Between ages 36 and 40, success was 69/147(47%) versus 22/98 (22%) controls (p < .0003), with 3 or more previous URSA live birth was 45/95 (47%) versus 6/46 (13%) controls (p < .0001). In UI, live birth was 99/298 (33%) versus 54/263 (21%) in controls (p < .0009) that increased under age 35 to 53/116 (46%) in treated versus 26/101 (26%) controls (p < .0056). In PIT treated, IVF success required a median of 1 (1.37 ± 0.67) versus a median of 3 IVF procedures (2.75 ± 0.84) in controls. CONCLUSION: PIT is a successful treatment for primary and secondary URSA, and UI. PIT reduced the number of IVF required for achieving pregnancy.

Human CD8+HLA-DR+ Regulatory T Cells, Similarly to Classical CD4+Foxp3+ Cells, Suppress Immune Responses via PD-1/PD-L1 Axis.

We have previously identified a human CD8+HLA-DR+ regulatory T cell subset with the ability to suppress proliferation of autologous PBMCs responder cells through cell contact and CTLA-4 co-inhibitory molecule. The present study characterizes the complete phenotype of CD8+HLA-DR+ Treg cells which showed great similarities with classical CD4+ cells expressing forkhead box P3 (FOXP3). The shared features included the expression of programmed cell death protein 1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), C-C chemokine receptor type 4 and 5 (CCR4 and CCR5), low expression of CD127, and a memory and effector-like phenotype. CD8+HLA-DR+ Treg-induced suppression on CD8+ responder T cells was abrogated by an anti-PD1 neutralizing antibody. Anti-PD-1 did not abrogate the suppressor effect induced on responder CD4+ T cells. In addition, CD8+HLA-DR+ Treg induced a preferential death on responder CD8+ T cells. This effect was not reversed by PD-1 neutralization. After activation, most CD8+HLA-DR+ Treg acquire programmed death-ligand 1 (PD-L1) expression. Interestingly, PD-L1 may induce apoptosis through CD80 expressed on activated CD8+ responder T cells. After PBMCs stimulation, CD8+HLA-DR+ Treg cells showed an increased frequency of IFN-γ and TNFα positive cells and higher degranulation. These data strongly argue against CD8+HLA-DR+ Treg being exhausted cells. Overall, the data presented in this study indicate that CD8+HLA-DR+ Treg and CD4+FOXP3+ Treg share phenotypic and functional features, which may provide cues to similar involvements in the control of antitumor immune responses and autoimmunity.

The Clinical Features of Patients with Chronic Hepatitis C Virus Infections Are Associated with Killer Cell Immunoglobulin-Like Receptor Genes and Their Expression on the Surface of Natural Killer Cells.

Killer cell immunoglobulin-like receptor (KIR) genes are known to play a role in the acute phase of hepatitis C virus (HCV) infection. The present study investigated their roles in chronic HCV (CHCV) infection by analyzing the phenotypes and function of natural killer (NK) and T cells that express KIRs. T cells from CHCV patients showed a more differentiated phenotype, and NK cells exhibited an activated profile. These observations are consistent with the increased expression of the degranulation marker CD107a observed after PMA stimulation. We explored the correlations between the expression of KIR genes and lectin type-C receptors with clinical factors that predict progression to fibrosis and cirrhosis. The expression levels of KIR2DS3 and the functional alleles of KIR2DS4-FL were increased in patients with intermediate and high viral loads. Homozygous KIR2DS4 was also associated with the presence of cirrhosis. In the group of individuals with a shorter infection time who developed cirrhosis, we detected decreased expression of KIR3DL1 in CD56dim NK cells in the presence of its ligand. Similarly, in the group of patients with late CHCV infections complicated with cirrhosis, we detected lower expression of the strong inhibitory receptor NKG2A in CD56bright NK cells. We also detected an increase in NKG2C expression in CD56dim NK cells in CHCV patients who displayed high necroinflammatory activity. Decreased KIR3DL2 expression in CD56dim and CD56bright NK cells was associated with a high body mass index, and KIR3DL2 expression may be one factor associated with the more rapid progression of CHCV to fibrosis in patients.