Chronic viral infections lead to persistent CD8 T cell activation and functional exhaustion. Expression of programmed cell death-1 (PD-1) has been associated to CD8 T cell dysfunction in HIV infection. Herein we report that another negative regulator of T cell activation, CD160, was also upregulated on HIV-specific CD8 T lymphocytes mostly during the chronic phase of infection. CD8 T cells that expressed CD160 or PD-1 were still functional whereas co-expression of CD160 and PD-1 on CD8 T cells defined a novel subset with all the characteristics of functionally exhausted T cells. Blocking the interaction of CD160 with HVEM, its natural ligand, increased HIV-specific CD8 T cell proliferation and cytokine production. Transcriptional profiling showed that CD160−PD-1+CD8 T cells encompassed a subset of CD8+ T cells with activated transcriptional programs, while CD160+PD-1+ T cells encompassed primarily CD8+ T cells with an exhausted phenotype. The transcriptional profile of CD160+PD-1+ T cells showed the downregulation of the NFκB transcriptional node and the upregulation of several inhibitors of T cell survival and function. Overall, we show that CD160 and PD-1 expressing subsets allow differentiating between activated and exhausted CD8 T cells further reinforcing the notion that restoration of function will require multipronged approaches that target several negative regulators.
Carriage of the natural killer (NK) receptor genotype KIR3DL1*h/*y with its HLA-B*57 ligand (*h/*y+B*57) is associated with slow time to AIDS and low viral load (VL). To provide a functional basis for these epidemiological observations, we assessed whether HIV-1-infected slow progressors (SP) carrying the *h/*y+B*57 compound genotype would have increased NK cell polyfunctional potential in comparison to SP with other killer immunoglobulin-like receptor (KIR)/HLA compound genotypes and whether this enhanced polyfunctionality was dependent upon the coexpression of both KIR3DL1*h/*y and HLA-B*57. The functional potential of NK cells was investigated by stimulating peripheral blood mononuclear cells with HLA-devoid targets or single HLA transfectants. Multiparametric flow cytometry was used to detect NK cells with seven functional profiles representing all permutations of CD107a expression and gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) secretion. NK cells from individuals carrying KIR3DL1 receptor–HLA-Bw4 ligand pairs had greater trifunctional responses than those from KIR3DL1 homozygotes (hmz), who were Bw6 homozygotes. NK cells from subjects carrying the *h/*y+B*57 genotypes exhibited the highest trifunctional potential, and this was dependent on cocarriage of the NK receptor and its ligand. Trifunctional cells secreted more of each function tested on a per-cell basis than each corresponding monofunctional NK subset. Although VL influenced NK functionality, individuals with defined KIR/HLA genotypes exhibited differences in NK cell polyfunctionality that could not be accounted for by VL alone. The protective effect of HLA-B*57 on slow progression to AIDS and low VL may be mediated through its interaction with KIR3DL1 alleles to educate NK cells for potent activity upon stimulation.
In chronic HIV infection, most untreated patients lose naive CD4 ؉ and CD8 ؉ T cells, whereas a minority preserve them despite persistent high viremia. Although antiretroviral therapy (ART)-mediated viral suppression generally results in a rise of naive and total CD4 ؉ T cells, certain patients experience very little or no T-cell reconstitution. High peripheral T-cell activation has been linked to poor clinical outcomes, interfering with previous evaluations of thymic function in disease progression and therapy-mediated T-cell recovery. To circumvent this, we used the sj/TREC ratio, a robust index of thymopoiesis that is independent of peripheral T-cell proliferation, to evaluate the thymic contribution to the preservation and restoration of naive CD4 ؉ T cells. We show that the loss of naive and total CD4 ؉ T cells is the result of or is exacerbated by a sustained thymic defect, whereas efficient thymopoiesis supports naive and total CD4 ؉ T-cell maintenance in slow progressor patients. In ART-treated patients, CD4 ؉ T-cell recovery was associated with the normalization of thymopoiesis, whereas the thymic defect persisted in aviremic patients who failed to recover CD4 ؉ T-cell counts. Overall, we demonstrate that efficient thymopoiesis is key in the natural maintenance and in therapymediated recovery of naive and total CD4 ؉ T cells. (Blood. 2007;109:2912-2920)
SummaryInterleukin (IL)-7 and its receptor (IL-7Ra) play important roles in regulating lymphopoiesis. Previous studies have reported that human immunodeficiency virus-1 (HIV-1) viraemia affects the expression of IL-7Ra, but its effects on CD4 + and CD8 + T cell memory subsets have not been studied. Using eight-colour flow cytometry, we compared the immunophenotypic patterns of CD4+ and CD8 + T cell subsets expressing IL-7Ra and activation markers, as well as circulating IL-7 levels, in three well-defined groups of HIV-1-infected subjects: successfully treated, viraemic and long-term non-progressor (LTNP). Compared with successfully treated and LTNP subjects, viraemic patients had reduced expression of IL-7Ra on both CD4+ and CD8 + T cells, particularly on central and effector memory T cell compartments, and substantially elevated expression of activation markers on CD8 + T cell subsets. Circulating IL-7 levels were correlated negatively with the number of CD4 +
and CD8+ T cell subsets expressing IL-7Ra; these associations were stronger with CD4 + T cell subsets and mainly with central and effector memory cells.
The expression of activation markers on CD4+ and CD8 + cell T subsets was not related to circulating IL-7 levels. A strong negative correlation was observed between central memory CD4 + or CD8 + T cells expressing IL-7Ra and those expressing activation markers, independently of IL-7 levels. Collectively, these results provide further insight on the role of unsuppressed viral load in disrupting the IL-7/IL-7Ra system and contributing to HIV-1 disease progression.
It has been shown that sera from patients with autoimmune inner ear disease contain antibodies to several inner ear antigens. We report here the characterization of the 42-43 kDa protein against which a significant number of patients' sera react strongly. After separation of inner ear proteins from guinea-pig cochleas by SDS-PAGE, the band corresponding to the 42-43 kDa protein was digested with trypsin and the peptide fragments were separated by high-performance liquid chromatography. Two fractions were then subjected to amino acid sequencing by the classical automated Edman degradation. The sequence of a stretch of 15 amino acids of the first fragment was identical to that of amino acids 148-162 of beta-actin. The sequence of the 10 amino acids of the second fragment was also identical to beta-actin. On Western blots, monoclonal antibody directed against beta-actin reacted with the inner ear 42-43 kDa proteins. The serum samples from the patients and the monoclonal antibody reacted with the non-muscle actin used as antigen in Western blotting. Immunoblot analysis of inner ear proteins after two-dimensional gel electrophoresis showed a spot, corresponding to the region of the 43 kDa as compared to the protein standards. On the basis of these data it is concluded that the target 42-43 kDa protein for antibodies in sera of patients with autoimmune inner ear disease is beta-actin, a molecule, which has important and numerous functions inside cells. This is the first report to identify the cytoskeletal protein beta-actin as a candidate autoantigen in autoimmune inner ear disease.
These findings indicate that the 58-kDa target protein of antibodies in serum samples of patients with autoimmune inner ear diseases is the COCH5B2 protein, a molecule that is highly and specifically expressed in the cochlea and vestibule.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.